Bis-Acylated Hydroxylamine Derivatives

ABSTRACT

The invention provides certain bis-acylated hydroxylamine derivative compounds, pharmaceutical compositions and kits comprising such compounds, and methods of using such compounds or pharmaceutical compositions. In particular, the invention provides methods of using such compounds or pharmaceutical compositions for treating, preventing, or delaying the onset and/or develop of a disease or condition. In some embodiments, the disease or condition is selected from cardiovascular diseases, ischemia, reperfusion injury, cancerous disease, pulmonary hypertension and conditions responsive to nitroxyl therapy.

This application claims the benefit of U.S. Provisional Application No.61/267,399, filed on Dec. 7, 2009, and U.S. Provisional Application No.61/291,224, filed on Dec. 30, 2009, the entire contents of whichapplications are hereby incorporated by reference.

CONGESTIVE HEART FAILURE (CHF)

Congestive heart failure (CHF) is a generally progressive, lifethreatening condition in which myocardial contractility is depressedsuch that the heart is unable to adequately pump the blood returning toit, also referred to as decompensation. Symptoms include breathlessness,fatigue, weakness, leg swelling, and exercise intolerance. On physicalexamination, patients with heart failure often have elevated heart andrespiratory rates (an indication of fluid in the lungs), edema, jugularvenous distension, and/or enlarged hearts. The most common cause of CHFis atherosclerosis, which causes blockages in the coronary arteries thatprovide blood flow to the heart muscle. Ultimately, such blockages maycause myocardial infarction with subsequent decline in heart functionand resultant heart failure. Other causes of CHF include valvular heartdisease, hypertension, viral infections of the heart, alcoholconsumption, and diabetes. Some cases of CHF occur without clearetiology and are called idiopathic. The effects of CHF on an individualexperiencing the condition can be fatal.

There are several types of CHF. Two types of CHF are identifiedaccording to which phase of the cardiac pumping cycle is more affected.Systolic heart failure occurs when the heart's ability to contractdecreases. The heart cannot pump with enough force to push a sufficientamount of blood into the circulation leading to a reduced leftventricular ejection fraction. Lung congestion is a typical symptom ofsystolic heart failure. Diastolic heart failure refers to the heart'sinability to relax between contractions and allow enough blood to enterthe ventricles. Higher filling pressures are required to maintaincardiac output, but contractility as measured by left ventricularejection fraction is typically normal. Swelling (edema) in the abdomenand legs is a typical symptom of diastolic heart failure. Often, anindividual experiencing heart failure will have some degree of bothsystolic heart failure and diastolic heart failure.

CHF is also classified according to its severity. The New York HeartAssociation classifies CHF into four classes: Class I involves noobvious symptoms, with no limitations on physical activity; Class IIinvolves some symptoms during or after normal activity, with mildphysical activity limitations; Class III involves symptoms with lessthan ordinary activity, with moderate to significant physical activitylimitations; and Class IV involves significant symptoms at rest, withsevere to total physical activity limitations. Typically, an individualprogresses through the classes as they live with the condition.

Although CHF is generally thought of as a chronic, progressivecondition, it can also develop suddenly. This type of CHF is calledacute CHF, and it is a medical emergency. Acute CHF can be caused byacute myocardial injury that affects either myocardial performance, suchas myocardial infarction, or valvular/chamber integrity, such as mitralregurgitation or ventricular septal rupture, which leads to an acuterise in left ventricular and diastolic pressure resulting in pulmonaryedema and dyspnea.

Common treatment agents for CHF include vasodilators (drugs that dilateblood vessels), positive inotropes (drugs that increase the heart'sability to contract), and diuretics (drugs to reduce fluid).Additionally, beta-antagonists (drugs that antagonize beta-adrenergicreceptors) have become standard agents for treating mild to moderateheart failure. Lowes et al., Clin. Cardiol. 2000, 23, III, 1-6.

Positive inotropic agents include beta-adrenergic agonists, such asdopamine, dobutamine, dopexamine, and isoproterenol. However, use of abeta-agonist has potential complications, such as arrhythmogenesis andincreased oxygen demand by the heart. Additionally, the initialshort-lived improvement of myocardial contractility afforded by thesedrugs is followed by an accelerated mortality rate resulting largelyfrom a greater frequency of sudden death. Katz, Heart Failure:Pathophysiology, Molecular Biology And Clinical Management 1999,Lippincott, Williams & Wilkins.

Beta-antagonists antagonize beta-adrenergic receptor function. Whileinitially contra-indicated in heart failure, they have been found toprovide a marked reduction in mortality and morbidity in clinicaltrials. Bouzamondo et al., Fundam. Clin. Pharmacol. 2001, 15, 95-109.Accordingly, they have become an established therapy for heart failure.However, even individuals that improve under beta-antagonist therapy maysubsequently decompensate and require acute treatment with a positiveinotropic agent. Unfortunately, as their name suggests, beta-antagonistsblock the mechanism of action of the positive inotropic beta-agoniststhat are used in emergency care centers. Bristow et al., J. Card. Fail.2001, 7, 8-12.

Vasodilators, such as nitroglycerin, have been used for a long period oftime to treat heart failure. However, the cause of nitroglycerin'stherapeutic effect was not known until late in the last century when itwas discovered that the nitric oxide molecule (NO) was responsible fornitroglycerin's beneficial effects. In some individuals experiencingheart failure, a nitric oxide donor is administered in combination witha positive inotropic agent to both cause vasodilation and to increasemyocardial contractility. However, this combined administration canimpair the effectiveness of positive inotropic treatment agents. Forexample, Hart et al, Am. J. Physiol. Heart Circ. Physiol. 2001, 281,146-54, reported that administration of the nitric oxide donor sodiumnitroprusside, in combination with the positive inotropic,beta-adrenergic agonist dobutamine, impaired the positive inotropiceffect of dobutamine. Hare et al., Circulation 1995, 92, 2198-2203, alsodisclosed the inhibitory effect of nitric oxide on the effectiveness ofdobutamine.

As described in U.S. Pat. No. 6,936,639, compounds that donate nitroxyl(HNO) under physiological conditions have both positive inotropic andlusotropic effects and offer significant advantages over existingtreatments for failing hearts. Due to their concomitant positiveinotropic/lusotropic action and unloading effects, nitroxyl donors werereported as helpful in treating cardiovascular diseases characterized byhigh resistive load and poor contractile performance. In particular,nitroxyl-donating compounds were reported as useful in the treatment ofheart failure, including heart failure in individuals receivingbeta-antagonist therapy.

Ischemia

Ischemia is a condition characterized by an interruption or inadequatesupply of blood to tissue, which causes oxygen deprivation in theaffected tissue. Myocardial ischemia is a condition caused by a blockageor constriction of one or more of the coronary arteries, such as canoccur with atherosclerotic plaque occlusion or rupture. The blockade orconstriction causes oxygen deprivation of the non-perfused tissue, whichcan cause tissue damage. Further, upon reperfusion with subsequentreoxygenation of the tissue, when the blood is able to flow again or theoxygen demand of the tissue subsides, additional injury can be caused byoxidative stress.

Ischemia/reperfusion injury refers to tissue damage caused by oxygendeprivation followed by reoxygenation. The effects ofischemia/reperfusion injury in an individual experiencing the conditioncan be fatal, particularly when the injury occurs in a critical organsuch as the heart or brain.

Accordingly, compounds and compositions effective in preventing orprotecting against ischemia/reperfusion injury would be usefulpharmaceuticals. Compounds such as nitroglycerin have been used for along period of time to help control vascular tone and protect againstmyocardial ischemia/reperfusion injury. It was discovered that thenitric oxide molecule was responsible for nitroglycerin's beneficialeffects. This discovery prompted interest in medical uses for nitricoxide and investigations into related species such as nitroxyl. Asreported in U.S. patent application Ser. No. 10/463,084 (U.S.Publication No. 2004/0038947), administration of a compound that donatesnitroxyl under physiological conditions, prior to ischemia, canattenuate ischemia/reperfusion injury to tissues, for example,myocardial tissues. This beneficial effect was reported as a surprisingresult given that nitroxyl was previously reported to increaseischemia/reperfusion injury (see, Ma et al., Proc. Natl Acad. Sci. 1999,96(25), 14617-14622, reporting that administration of Angeli's salt (anitroxyl donor under physiological conditions) to anesthetized rabbitsduring ischemia and 5 minutes prior to reperfusion increased myocardialischemia/reperfusion injury, and Takahira et al., Free Radical Biology &Medicine 2001, 31(6), 809-815, reporting that administration of Angeli'ssalt during ischemia and 5 minutes before reperfusion of rat renaltissue contributed to neutrophil infiltration into the tissue, which isbelieved to mediate ischemia/reperfusion injury). In particular,pre-ischemic administration of Angeli's salt and isopropylamine/NO hasbeen reported to prevent or reduce ischemia/reperfusion injury.

Cancer

One of the challenges in developing anti-cancer drugs is to discovercompounds that are selectively toxic to tumor cells over normal cells.It has been found that tumor tissues have an acidic microenvironmentwith a pH from 6.0 to 7.0, while the extra- and intracellular milieu ofnormal cells has a pH of 7.4. Angeli's salt has been reported to exhibitstrong cytotoxicity to cancer cells in weakly acidic solutions, whereasno toxicity was observed at pH 7.4 (Stoyanovsky, D. A. et al. J. Med.Chem. 2004, 47, 210-217; and PCT Publication No. WO/2003/020221). In asubcutaneous xenograft model of pheochromocytoma, Angeli's salt wasfound to inhibit tumor growth at a dose that was nontoxic to nude mice.Nitroxyl derivatives that are not known to release HNO, such as ruboxyl,a nitroxyl analogue of daunorubicin, have been shown to be activeagainst hepatic metastases from colorectal carcinoma (Sirovich, I. etal. Tumor Biol. 1999, 20, 270-276).

Norris A. J. et al., Intl. J. Cancer 2008, 122, 1905-1910, reported thatAngeli's salt inhibits the proliferation of cultured breast cancer cellsand decreases tumor mass in a mouse xenograft model. Norris A. J. et alproposed that HNO released from Angeli's salt blocks glycolysis incancer cells by inhibiting the enzyme glyceraldehyde 3-phosphatedehydrogenase (GAPDH), resulting in decreased levels of HIF-1α(hypoxia-inducible factor) protein and activity, lower VEGF (vascularendothelial growth factor) production, decreased tumor angiogenesis andan increase in apoptotic cells.

Pulmonary Hypertension

Pulmonary hypertension (PH) is a generic term for a group of conditionscharacterized by elevated blood pressure in the arteries of the lungs(pulmonary arteries). In patients with PH, characteristic changes occurwithin the pulmonary circulation. These changes include thickening ofthe linings and obstruction of the small pulmonary blood vessels. As aresult of these changes, pressure in the pulmonary circulation rises,and resistance in the blood flowing through the vessels increases. Thisincreased resistance puts a strain on the right side of the heart as itmust work harder to pump blood to the lungs. This strain can cause theheart to enlarge. Eventually, heart failure can develop.

The World Health Organization (WHO) classification of PH¹, as updated inthe 2008 4^(th) World Conference in Dana Point, Calif., includes fivegroups: pulmonary arterial hypertension (PAH)(Group 1), PH owing to leftheart disease (Group 2), PH owing to lung diseases and/or hypoxia (Group3), chronic thromboembolic PH (Group 4), and PH with unclearmultifactorial mechanisms (Group 5). ¹ The initial attempt to develop aclassification for PH was undertaken during the WHO Conference on PH in1973. Since then, the PH classification has been revised three times,first at the 1998 2^(nd) World Symposium in Evian, France, then at the2003 3^(rd) World Symposium in Venice, Italy, and most recently at the2008 4th World Symposium in Dana Point, Calif.

Notwithstanding the current WHO classification, some literature stillrefer to the older classification system of “primary” and “secondary”PH. Primary PH refers to idiopathic PH, while secondary PH refers to PHthat develops from another medical condition. For example, under theolder classification system, PH owing to left heart disease wasclassified as PH secondary to left heart disease.

Current therapies for PH include supplemental oxygen, diuretics, oralvasodilators such as calcium channel blockers, anticoagulants, inotropicagents, prostanoids, endothelin receptor antagonists, andphosphodiesterase type-5 inhibitors. While such therapies have met withsome success, many PH patients fail to respond to these therapies.

Nitroxyl Donors

Due to its inherent reactivity, HNO must be generated in situ from donorcompounds. To date, the vast majority of studies of the biologicaleffect of HNO have used the donor sodium α-oxyhyponitrite (“Angeli'ssalt” or “AS”). However, the chemical stability of AS has made itunsuitable to develop as a therapeutic agent. Angeli's salt alsoreleases nitrite, which possesses its own biological profile.N-hydroxybenzenesulfonamide (“Piloty's acid” or “PA”) has previouslybeen shown to be a nitroxyl donor only at high pH (>9) (Bonner, F. T. etal., Inorg. Chem. 1992, 31, 2514-2519). Under physiological conditions,PA has been shown to be a nitric oxide donor via an oxidative pathway(Zamora, R. et al., Biochem. J. 1995, 312, 333-339). PCT PatentApplication Publication No. WO/2007/109175 describesN-hydroxylsulfonamide derivatives that donate nitroxyl underphysiological conditions.

Acyloxy nitroso compounds have been reported to yield nitroxyl in situwhen reacted with nucleophiles (Sha, X. et al., J. Am. Chem. Soc. 2006,128, 9687-9692). Although Rehse et al., Arch. Pharm. Med. Chem. 1998,331, 104-110, showed acyloxy nitroso compounds inhibit plateletaggregation and thrombus formation (indicative of NO release), theygenerate only small amounts (<1%) of NO and HNO under neutralconditions. International Patent Application Publication WO 2007/120839describes conjugates of acyloxy nitroso compounds with non-steroidalanti-inflammatory drugs (NSAID) as nitroxyl donors for treatingcongestive heart failure.

Significant Medical Need

Despite efforts towards the development of new therapies for thetreatment of the diseases and conditions described above, there remainsa significant medical need for additional or alternative compounds thattreat, prevent or delay the onset and/or development of these andrelated diseases or conditions. In particular, there remains asignificant medical need for alternative or additional therapies for thetreatment of diseases or conditions that are responsive to nitroxyltherapy. New compounds that donate nitroxyl under physiologicalconditions and methods of using compounds that donate nitroxyl underphysiological conditions may thus find use as therapies for treating,preventing and/or delaying the onset and/or development of diseases orconditions responsive to nitroxyl therapy, including heart disease,ischemia/reperfusion injury and cancer. Preferably, the therapeuticagents can improve the quality of life and/or prolong the survival timefor patients with the disease or condition.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the intravenous effects of a nitroxyl (HNO) donor on meanand systolic (peak) pulmonary artery pressure (PAP) in rats.

FIG. 2 shows the intravenous effects of a nitroxyl (HNO) donor on meanarterial pressure (MPAP) and heart rate in rats.

FIG. 3 shows the intravenous effects of a nitroxyl (HNO) donor on meanchange in systolic pulmonary arterial pressure (SPAP) during hypoxicperiod relative to normoxic period compared to sildenafil citrate indogs.

DEFINITIONS

Unless clearly indicated otherwise, the following terms as used hereinhave the meanings indicated below.

“A”, “an” and the like refers to one or more.

“Eq” or “equiv” or “equivalent” refers to molar equivalent.

“Hr” or “h” refers to hour.

“Min” or “m” refers to minute.

“Alkyl” intends linear hydrocarbon structures having 1 to 20 carbonatoms, 1 to 12 carbon atoms or 1 to 8 carbon atoms. Alkyl groups offewer carbon atoms are embraced, such as so-called “lower alkyl” groupshaving 1 to 4 carbon atoms. “Alkyl” also intends branched or cyclichydrocarbon structures having 3 to 20 carbon atoms, 3 to 12 carbon atomsand 3 to 8 carbon atoms. For any use of the term “alkyl,” unless clearlyindicated otherwise, it is intended to embrace all variations of alkylgroups disclosed herein, as measured by the number of carbon atoms, thesame as if each and every alkyl group was explicitly and individuallylisted for each usage of the term. For instance, when a group such as R³may be an “alkyl,” intended is a C₁-C₂₀ alkyl or a C₁-C₁₂ alkyl or aC₁-C₈ alkyl or a lower alkyl or a C₂-C₂₀ alkyl or a C₃-C₁₂ alkyl or aC₃-C₈ alkyl. The same is true for other groups listed herein, which mayinclude groups under other definitions, where a certain number of atomsis listed in the definition. When the alkyl group is cyclic, it may alsobe referred to as a cycloalkyl group and have, for example, 1 to 20annular carbon atoms, 1 to 12 annular carbon atoms and 1 to 8 annularcarbon atoms. When an alkyl residue having a specific number of carbonsis named, all geometric isomers having that number of carbons areintended to be encompassed; thus, for example, “butyl” is meant toinclude n-butyl, sec-butyl, iso-butyl and t-butyl; “propyl” includesn-propyl and iso-propyl. Examples of alkyl groups include methyl, ethyl,n-propyl, i-propyl, t-butyl, n-heptyl, octyl, cyclopentyl, cyclopropyl,cyclobutyl, norbornyl, and the like.

“Substituted alkyl” refers to an alkyl group having from 1 to 5substituents. For instance, an alkyl group substituted with a group suchas halo, nitro, cyano, oxo, aryl, alkoxy, acyl, acylamino, amino,hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkyl, heterocyclyl,—OS(O)₂-alkyl, and the like is a substituted alkyl. Likewise,“substituted alkenyl” and “substituted alkynyl” refer to alkenyl oralkynyl groups having 1 to 5 substituents.

“Substituted” means that a hydrogen radical on a compound or group (suchas, for example, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, aralkyl,substituted aralkyl, heteroaryl, substituted heteroaryl, heteroaralkyl,substituted heteroaralkyl, cycloalkyl, substituted cycloalkyl,heterocycloalkyl, substituted heterocycloalkyl, heterocyclyl andsubstituted heterocyclyl) is replaced with a group (the “substituent”)that does not substantially adversely affect the stability of thecompound. In some embodiments, the substituents are those which do notadversely affect the activity of a compound. The term “substituted”refers to one or more substituents (which may be the same or different),each replacing a hydrogen atom. Examples of substituents include, butare not limited to, halo (F, Cl, Br, or I), hydroxyl, amino, alkylamino,arylamino, dialkylamino, diarylamino, cyano, nitro, mercapto, oxo,carbonyl, thio, imino, formyl, carbamido, carbamyl, carboxyl,thioureido, thiocyanato, sulfoamido, sulfonylalkyl, sulfonylaryl, alkyl,alkenyl, alkoxy, mercaptoalkoxy, aryl, heteroaryl, cyclyl, heterocyclyl,wherein alkyl, alkenyl, alkyloxy, aryl, heteroaryl, cyclyl, andheterocyclyl are optionally substituted with alkyl, aryl, heteroaryl,halogen, hydroxyl, amino, mercapto, cyano, nitro, oxo (═O), thioxo (═S),or imino (═Nalkyl). In some embodiments, substituents on any group (suchas, for example, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, aralkyl,substituted aralkyl, heteroaryl, substituted heteroaryl, heteroaralkyl,substituted heteroaralkyl, cycloalkyl, substituted cycloalkyl,heterocycloalkyl, substituted heterocycloalkyl, heterocyclyl andsubstituted heterocyclyl) are at any atom of that group (such as on acarbon atom of the primary carbon chain of a substituted alkyl group oron a substituent already present on a substituted alkyl group), whereinany group that can be substituted (such as, for example, alkyl, alkenyl,alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cyclyl,heterocycloalkyl, and heterocyclyl) can be optionally substituted withone or more substituents (which may be the same or different), eachreplacing a hydrogen atom. Examples of substituents include, but notlimited to alkyl, alkenyl, alkynyl, cyclyl, cycloalkyl, heterocyclyl,heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo,haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxyl, hydroxylalkyl, oxo,carbonyl, carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl,alkoxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy,heteroaryloxycarbonyl, thio, mercapto, mercaptoalkyl, arylsulfonyl,amino, aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl,or alkoxycarbonylamino; alkylamino, arylamino, diarylamino,alkylcarbonyl, or arylamino-substituted aryl; arylalkylamino,aralkylaminocarbonyl, amido, alkylaminosulfonyl, arylaminosulfonyl,dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, imino,carbamido, carbamyl, thioureido, thiocyanato, sulfoamido, sulfonylalkyl,sulfonylaryl, or mercaptoalkoxy. Additional examples of substituentsinclude, without limitation, halo, CN, NO₂, OR¹¹, SR¹¹, S(O)₂OR¹¹,NR¹¹R¹², C₁-C₂ perfluoroalkyl, C₁-C₂ perfluoroalkoxy,1,2-methylenedioxy, (═O), (═S), (═NR¹¹), O(CH₂)_(n)OR¹¹, C(O)R¹¹,C(O)OR¹¹, C(OR¹¹)R¹², C(O)NR¹¹R¹², OC(O)R¹³, OC(O)NR¹¹R¹²,NR¹¹C(O)NR¹¹R¹², C(NR¹²)NR¹¹R¹², NR¹¹C(NR¹²)NR¹¹R¹², S(O)₂NR₁₁R¹²R¹³,C(O)H, C(O)R¹³, NR¹¹C(O)R¹³, NR¹¹C(O)OR¹³, Si(R¹¹)₃, OSi(R¹¹)₃,Si(OH)₂R¹¹, B(OH)₂, P(O)(OR¹¹)₂, S(O)R¹³, and S(O)₂R¹³. Each R¹¹ isindependently hydrogen, C₁-C₆ alkyl optionally substituted with alkoxy,cycloalkyl, aryl, heterocyclyl, or heteroaryl. Each R¹² is independentlyhydrogen, C₃-C₆ cycloalkyl, aryl, heterocyclyl, heteroaryl, C₁-C₄ alkylor C₁-C₄ alkyl substituted with C₃-C₆ cycloalkyl, aryl, heterocyclyl orheteroaryl. Each R¹³ is independently C₃-C₆ cycloalkyl, aryl,heterocyclyl, heteroaryl, C₁-C₄ alkyl or C₁-C₄ alkyl substituted withC₃-C₆ cycloalkyl, aryl, heterocyclyl or heteroaryl. Each C₃-C₆cycloalkyl, aryl, heterocyclyl, heteroaryl and C₁-C₄ alkyl in each R¹¹,R¹² and R¹³ can optionally be substituted with halo, CN, C₁-C₄ alkyl,OH, C₁-C₄ alkoxy, COOH, C(O)OC₁-C₄ alkyl, NH₂, C₁-C₄ alkylamino, orC₁-C₄ dialkylamino. Each n is an integer from 1 to 6. Substituents canalso be “electron-withdrawing groups.”

“Alkenyl” refers to a group of 2 or more carbon atoms, such as 2 to 10carbon atoms and 2 to 6 carbon atoms, and having at least one doublebond. Examples of an alkenyl group include —C═CH2, —CH2CH═CHCH3 and—CH2CH═CH—CH═CH2.

“Alkynyl” refers to group having 2 or more carbon atoms, such as 2 to 10carbon atoms and 3 to 6 carbon atoms, and having at least one triplebond, such as the moiety —C≡CH.

“Heterocyclyl” or “heterocycloalkyl” refers to a cycloalkyl residue inwhich one to four of the carbons is replaced by a heteroatom such asoxygen, nitrogen or sulfur. Examples of heterocycles whose radicals areheterocyclyl groups include tetrahydropyran, morpholine, pyrrolidine,piperidine, thiazolidine, oxazole, oxazoline, isoxazole, dioxane,tetrahydrofuran and the like. A specific example of a heterocyclylresidue is tetrahydropyran-2-yl.

“Substituted heterocylyl” or “substituted heterocylcoalkyl” refers to anheterocyclyl group having from 1 to 5 substituents. For instance, aheterocyclyl group substituted with 1 to 5 groups such as halo, nitro,cyano, oxo, aryl, alkoxy, alkyl, acyl, acylamino, amino, hydroxyl,carboxyl, carboxyalkyl, thiol, thioalkyl, heterocyclyl, —OS(O)₂-alkyl,and the like is a substituted alkyl. A particular example of asubstituted heterocylcoalkyl is N-methylpiperazino.

“Aryl” refers to a monocyclic, bicyclic or tricyclic aromatic ringradical. In some embodiments, an aryl group is a 5- or 6-memberedaromatic ring containing; a bicyclic 9- or 10-membered aromatic ringsystem (meaning the ring system has 9 or 10 annular atoms); or atricyclic 13- or 14-membered aromatic ring system (meaning the ringsystem has 13 or 14 annular atoms). Examples of aryl radicals include,for example, phenyl, naphthalenyl, indanyl and tetralinyl.

“Substituted aryl” refers to a group having from 1 to 3 substituents.For instance, an aryl group substituted with 1 to 3 groups, such ashalo, nitro, cyano, oxo, aryl, alkoxy, alkyl, acyl, acylamino, amino,hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkyl, heterocyclyl,—OS(O)₂-alkyl and the like, is a substituted aryl.

“Aralkyl” refers to a residue in which an aryl moiety is attached to theparent structure via an alkyl residue. Examples include benzyl(—CH₂-Ph), phenethyl (—CH₂CH₂Ph), phenylvinyl (—CH═CH-Ph), phenylallyland the like.

“Heteroaryl” refers to an aromatic ring system having at least oneannular heteroatom selected from O, N, or S. An heteroaryl group ispreferably a 5- or 6-membered aromatic ring containing 1-3 annularheteroatoms selected from O, N, or S; a bicyclic 9- or 10-memberedaromatic ring system (meaning the ring system has 9 or 10 annular atoms)containing 1-3 annular heteroatoms selected from O, N, or S; or atricyclic 13- or 14-membered aromatic ring system (meaning the ringsystem has 13 or 14 annular atoms) containing 1-3 annular heteroatomsselected from O, N, or S. Examples of groups whose radicals areheteroaryl groups include e.g., imidazole, pyridine, indole, thiophene,benzopyranone, thiazole, furan, benzimidazole, benzoxazole,benzthiazole, quinoline, isoquinoline, quinoxaline, pyrimidine,pyrazine, tetrazole and pyrazole.

“Alkoxy” refers to an alkyl group that is connected to the parentstructure through an oxygen atom (—O-alkyl). When a cycloalkyl group isconnected to the parent structure through an oxygen atom, the group mayalso be referred to as a cycloalkoxy group. Examples include methoxy,ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.When the cylcoalkyl group contains one or more heteroatoms, the groupmay also be referred to as “heterocycloalkoxy” group. Examples ofheteroatoms include O, S, N, P, Se, Si and the like. A “perhaloalkoxy”intends a perhaloalkyl group attached to the parent structure through anoxygen, such as the residue —O—CF₃.

“Aryloxy” refers to an aryl group that is connected to the parentstructure through an oxygen atom (—O-aryl), which by way of exampleincludes the residues phenoxy, naphthoxy, and the like. “Substitutedaryloxy” refers to a substituted aryl group connected to the parentstructure through an oxygen atom (—O-substituted aryl).

“Electron withdrawing group” refers to a group that reduces electrondensity of the moiety to which it is attached (relative to the densityof the moiety without the substituent). Examples include, withoutlimitation, F, Cl, Br, I, —CN, —CF₃, —NO₂, —SH, —C(O)H, —C(O)alkyl,—C(O)Oalkyl, —C(O)OH, —C(O)Cl, —S(O)₂OH, —S(O)₂NHOH, —NH₃ and the like.

“Halo” refers to fluoro, chloro, bromo or iodo.

“Alkylsulfonyl” refers to groups —SO₂alkyl and —SO₂substituted alkyl,which includes the residues —SO₂cycloalkyl, —SO₂substituted cycloalkyl,—SO₂alkenyl, —SO₂substituted alkenyl, —SO₂alkynyl, —SO₂substitutedalkynyl, where alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl and substituted cycloalkyl areas defined herein.

“N-hydroxylsulfonamidyl” refers to —S(O)₂NROH, where R is H or alkyl.

“Perhaloalkyl” refers to an alkyl group where each H of the hydrocarbonis replaced with F. Examples of perhalo groups include —CF₃ and —CF₂CF₃.

“Alkylsulfanyl” refers to an alkyl group that is connected to the parentstructure through a sulfur atom (—S-alkyl) and refers to groups —S-alkyland —S-substituted alkyl, which include the residues —S-cycloalkyl,—S-substituted cycloalkyl, —S-alkenyl, —S-substituted alkenyl,—S-alkynyl, and —S-substituted alkynyl, where alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyland substituted cycloalkyl are as defined herein. When a cycloalkylgroup is connected to the parent structure through an sulfur atom, thegroup may also be referred to as a cycloalkylsulfanyl group. By way ofexample, alkylsulfanyl includes —S—CH(CH₃), —S—CH₂CH₃ and the like.

“Alkylsulfinyl” refers to an alkyl group that is connected to the parentstructure through a S(O) moiety and refers to groups —S(O)alkyl and—S(O)substituted alkyl, which includes the residues —S(O)cycloalkyl,—S(O)substituted cycloalkyl, —S(O)alkenyl, —S(O)substituted alkenyl,—S(O)alkynyl, —S(O)substituted alkynyl, where alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyland substituted cycloalkyl are as defined herein. By way of example,alkylsulfinyl includes the residues —S(O)CH(CH₃), —S(O)CH₃,—S(O)cyclopentane and the like.

“Arylsulfinyl” refers to an aryl group that is connected to the parentstructure through a S(O) moiety, which by way of example includes theresidue —S(O)Ph.

“Acyl” refers to and includes the groups —C(O)H, —C(O)alkyl,—C(O)substituted alkyl, —C(O)alkenyl, —C(O)substituted alkenyl,—C(O)alkynyl, —C(O)substituted alkynyl, —C(O)cycloalkyl,—C(O)substituted cycloalkyl, —C(O)aryl, —C(O)substituted aryl,—C(O)heteroaryl, —C(O)substituted heteroaryl, —C(O)heterocyclic, and—C(O)substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein or otherwise known in the art.

“Dialkylamino” refers to the group —NR₂ where each R is an alkyl group.Examples of dialkylamino groups include —N(CH₃)₂, —N(CH₂CH₂CH₂CH₃)₂, andN(CH₃)(CH₂CH₂CH₂CH₃).

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where the event or circumstance occurs and instances in whichit does not. For example, an alkyl that is “optionally substituted”encompasses both an alkyl that is unsubstituted and an alkyl that issubstituted.

“Pharmaceutically acceptable” refers to those properties and/orsubstances that are acceptable to the patient from a pharmacologicaland/or toxicological point of view, and/or to the manufacturingpharmaceutical chemist from a physical and/or chemical point of viewregarding composition, formulation, stability, patient acceptance,bioavailability and compatibility with other ingredients.

“Pharmaceutically acceptable salt” refers to pharmaceutically acceptablesalts of a compound described herein, such as a compound of formula (I),(Ia) or (II) or other nitroxyl donors, which salts may be derived from avariety of organic and inorganic counter ions well known in the art andinclude, by way of example, sodium, potassium, calcium, magnesium,ammonium, tetraalkylammonium, and the like; when the molecule contains abasic functionality, salts of organic or inorganic acids, such ashydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate,oxalate and the like. Illustrative salts include, but are not limited,to sulfate, citrate, acetate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, lactate, salicylate, acid citrate,tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,succinate, maleate, besylate, fumarate, gluconate, glucaronate,saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, and p-toluenesulfonate salts.Accordingly, a salt may be prepared from a compound of any one of theformulae disclosed herein having an acidic functional group, such as acarboxylic acid functional group, and a pharmaceutically acceptableinorganic or organic base. Suitable bases include, but are not limitedto, hydroxides of alkali metals such as sodium, potassium, and lithium;hydroxides of alkaline earth metal such as calcium and magnesium;hydroxides of other metals, such as aluminum and zinc; ammonia, andorganic amines, such as unsubstituted or hydroxy-substituted mono-, di-,or trialkylamines; dicyclohexylamine; tributyl amine; pyridine;N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, ortris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, ortris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, ortris-(hydroxymethyl)methylamine, N,N,-di-lower alkyl-N-(hydroxy loweralkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl) amine, ortri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such asarginine, lysine, and the like. A salt may also be prepared from acompound of any one of the formulae disclosed herein having a basicfunctional group, such as an amino functional group, and apharmaceutically acceptable inorganic or organic acid. Suitable acidsinclude hydrogen sulfate, citric acid, acetic acid, hydrochloric acid(HCl), hydrogen bromide (HBr), hydrogen iodide (HI), nitric acid,phosphoric acid, lactic acid, salicylic acid, tartaric acid, ascorbicacid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconicacid, glucaronic acid, formic acid, benzoic acid, glutamic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, andp-toluenesulfonic acid.

“Pharmaceutically acceptable excipient” refers to any substance, notitself a therapeutic agent, used as a carrier, diluent, adjuvant,binder, and/or vehicle for delivery of a therapeutic agent to a patient,or added to a pharmaceutical composition to improve its handling orstorage properties or to permit or facilitate formation of a compound orcomposition into a unit dosage form for administration. Pharmaceuticallyacceptable excipients are well known in the pharmaceutical arts and aredescribed, for example, in Remington's Pharmaceutical Sciences, MackPublishing Co., Easton, Pa. (e.g., 20^(th) Ed., 2000), and Handbook ofPharmaceutical Excipients, American Pharmaceutical Association,Washington, D.C., (e.g., 1^(st), 2^(nd) and 3^(rd) Eds., 1986, 1994 and2000, respectively). As will be known to those skilled in the art,pharmaceutically acceptable excipients may provide a variety offunctions and may be described as wetting agents, buffering agents,suspending agents, lubricating agents, emulsifiers, disintegrants,absorbents, preservatives, surfactants, colorants, flavorants, andsweeteners. Examples of pharmaceutically acceptable excipients includewithout limitation: (1) sugars, such as lactose, glucose and sucrose;(2) starches, such as corn starch and potato starch; (3) cellulose andits derivatives, such as sodium carboxymethyl cellulose, ethylcellulose, cellulose acetate, hydroxypropylmethylcellulose, andhydroxypropylcellulose; (4) powdered tragacanth; (5) malt; (6) gelatin;(7) talc; (8) excipients, such as cocoa butter and suppository waxes;(9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil,olive oil, corn oil and soybean oil; (10) glycols, such as propyleneglycol; (11) polyols, such as glycerin, sorbitol, mannitol andpolyethylene glycol; (12) esters, such as ethyl oleate and ethyllaurate; (13) agar; (14) buffering agents, such as magnesium hydroxideand aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17)isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pHbuffered solutions; (21) polyesters, polycarbonates and/orpolyanhydrides; and (22) other non-toxic compatible substances employedin pharmaceutical formulations.

“Unit dosage form” refers to a physically discrete unit suitable as aunitary dosage for human or other animal patients. Each unit dosage formmay contain a predetermined amount of an active substance (e.g., acompound of formula (I), (Ia) or (II)) calculated to produce a desiredeffect.

Unless clearly indicated otherwise, an “individual” or “patient” refersto an animal, such as a mammal, including but not limited, to a human.Hence, the methods described herein can be useful in human therapy andveterinary applications. In some embodiments, the individual or patientis a mammal. In some embodiments, the individual or patient is a human.

“Effective amount” refers to such amount of a compound or apharmaceutically acceptable salt thereof, which in combination with itsparameters of efficacy and toxicity, as well as based on the knowledgeof the practicing specialist should be effective in a given therapeuticform. As is understood in the art, an effective amount may be in one ormore doses.

“Treatment” or “treating” is an approach for obtaining a beneficial ordesired result, including clinical results. For purposes of thisinvention, beneficial or desired results include but are not limited toinhibiting and/or suppressing the onset and/or development of a diseaseor condition or reducing the severity of such disease or condition, suchas reducing the number and/or severity of symptoms associated with thedisease or condition, increasing the quality of life of those sufferingfrom the disease or condition, decreasing the dose of other medicationsrequired to treat the disease or condition, enhancing the effect ofanother medication an individual is taking for the disease or condition,and prolonging survival of individuals having the disease or condition.

“Preventing” refers to reducing the probability of developing a disorderor condition in an individual who does not have, but is at risk ofdeveloping a disorder or condition. An individual “at risk” may or maynot have a detectable disease or condition, and may or may not havedisplayed a detectable disease or condition prior to the treatmentmethods described herein. “At risk” denotes that an individual has oneor more so-called risk factors, which are measurable parameters thatcorrelate with development of a disease or condition and are known inthe art. An individual having one or more of these risk factors has ahigher probability of developing the disease or condition than anindividual without these risk factor(s).

“Nitroxyl” refers to the species HNO.

“Nitroxyl donor” or “HNO donor” refers to a compound that donatesnitroxyl under physiological conditions. As used herein, nitroxyl donorsmay alternatively be referred to as “a compound” or “the compound.” Insome embodiments, the nitroxyl donor is capable of donating an effectiveamount of nitroxyl in vivo and has a safety profile indicating thecompound would be tolerated by an individual in the amount necessary toachieve a therapeutic effect. One of ordinary skill in the art would beable to determine the safety of administering particular compounds anddosages to live subjects. One of skill in the art may also determinewhether a compound is a nitroxyl donor by evaluating whether it releasesHNO under physiological conditions. Compounds are easily tested fornitroxyl donation with routine experiments. Although it is impracticalto directly measure whether nitroxyl is donated, several tests areaccepted for determining whether a compound donates nitroxyl. Forexample, the compound of interest can be placed in solution, for examplein phosphate buffered saline (PBS) or phosphate buffered solution at apH of about 7.4, in a sealed container. After sufficient time fordisassociation has elapsed, such as from several minutes to severalhours, the headspace gas is withdrawn and analyzed to determine itscomposition, such as by gas chromatography and/or mass spectroscopy. Ifthe gas N₂O is formed (which occurs by HNO dimerization), the test ispositive for nitroxyl donation and the compound is a nitroxyl donor. Thelevel of nitroxyl donating ability may be expressed as a percentage of acompound's theoretical maximum. A compound that donates a “significantlevel of nitroxyl” intends a compound that donates 40% or more or 50% ormore of its theoretical maximum amount of nitroxyl. In some embodiments,the compounds for use herein donate 60% or more of the theoreticalmaximum amount of nitroxyl. In some embodiments, the compounds for useherein donate 70% or more of the theoretical maximum amount of nitroxyl.In some embodiments, the compounds for use herein donate 80% or more ofthe theoretical maximum amount of nitroxyl. In some embodiments, thecompounds for use herein donate 90% or more of the theoretical maximumamount of nitroxyl. In some embodiments, the compounds for use hereindonate between about 70% and about 90% of the theoretical maximum amountof nitroxyl. In some embodiments, the compounds for use herein donatebetween about 85% and about 95% of the theoretical maximum amount ofnitroxyl. In some embodiments, the compounds for use herein donatebetween about 90% and about 95% of the theoretical maximum amount ofnitroxyl. Compounds that donate less than 40% or less than 50% of theirtheoretical amount of nitroxyl are still nitroxyl donors and may be usedin the invention disclosed herein. A compound that donates less than 50%of the theoretical amount of nitroxyl may be used in the methodsdescribed, and may require higher dosing levels as compared to compoundsthat donate a significant level of nitroxyl. Nitroxyl donation also canbe detected by exposing the test compound to metmyoglobin (Mb³⁺).Nitroxyl reacts with Mb³⁺ to form an Mb²⁺-NO complex, which can bedetected by changes in the ultraviolet/visible spectrum or by ElectronParamagnetic Resonance (EPR). The Mb²⁺-NO complex has an EPR signalcentered around a g-value of about 2. Nitric oxide, on the other hand,reacts with Mb³⁺ to form an Mb³⁺-NO complex that is EPR silent.Accordingly, if the candidate compound reacts with Mb³⁺ to form acomplex detectable by common methods, such as ultraviolet/visible orEPR, then the test is positive for nitroxyl donation. Testing fornitroxyl donation may be performed at physiologically relevant pH.Examples of nitroxyl donors include, without limitation, sodiumdioxotrinitrate (“Angeli's salt” or “AS”), N-hydroxybenzenesulfonamide(“Piloty's acid” or “PA”), and the compounds disclosed in U.S. Pat. No.6,936,639, US Patent Publication Nos. 2004/0038947, 2007/0299107 and2009/0163487, and PCT Publication Nos. WO/2007/002444, WO/2005/074598and WO/2009/137717, the entire disclosures of which patents andpublications are herein incorporated by reference.

“Positive inotrope” refers to an agent that causes an increase inmyocardial contractile function. Such an agent includes abeta-adrenergic receptor agonist, an inhibitor of phosphodiesteraseactivity, and calcium-sensitizers. Beta-adrenergic receptor agonistsinclude, among others, dopamine, dobutamine, terbutaline, andisoproterenol. Analogs and derivatives of such compounds are alsointended. For example, U.S. Pat. No. 4,663,351 describes a dobutamineprodrug that can be administered orally. One of ordinary skill in theart would be able to determine if a compound is capable of causingpositive inotropic effects and also additional beta-agonist compounds.In particular embodiments, the beta-receptor agonist is selective forthe beta-1 receptor. In other embodiments the beta-agonist is selectivefor the beta-2 receptor, or is not selective for any particularreceptor.

Diseases or conditions that are “responsive to nitroxyl therapy”includes any disease or condition in which administration of a compoundthat donates an effective amount of nitroxyl under physiologicalconditions treats and/or prevents the disease or condition, as thoseterms are defined herein. A disease or condition whose symptoms aresuppressed or diminished upon administration of nitroxyl donor is adisease or condition responsive to nitroxyl therapy. Non-limitingexamples of diseases or conditions that are responsive to nitroxyltherapy include coronary obstructions, coronary artery disease (CAD),angina, heart attack, myocardial infarction, high blood pressure,ischemic cardiomyopathy and infarction, diastolic heart failure,pulmonary congestion, pulmonary edema, cardiac fibrosis, valvular heartdisease, pericardial disease, circulatory congestive states, peripheraledema, ascites, Chagas' disease, ventricular hypertrophy, heart valvedisease, heart failure, including but not limited to congestive heartfailure such as acute congestive heart failure and acute decompensatedheart failure. Other cardiovascular diseases or conditions are alsointended, as are diseases or conditions that implicateischemia/reperfusion injury. Cancer is another example of disease orcondition that is responsive to nitroxyl therapy.

“Pulmonary hypertension” or “PH” refers to a condition in which thepulmonary arterial pressure is elevated. The current haemodynamicdefinition of PH is a mean pulmonary arterial pressure (MPAP) at rest ofgreater than or equal to 25 mmHg.² Examples of PH include, but are notlimited to, the conditions listed in the updated classification of PH(Table 1).³ ² Badesch D. et al. Diagnosis and assessment of pulmonaryarterial hypertension. J Am Coll Cardiol 2009; 54(Suppl.): S55-S66.³Simonneau G. et al. Updated clinical classification of pulmonaryhypertension. J Am Coll Cardiol 2009; 54(1 Suppl): S43-54.

TABLE 1 Classification of Pulmonary Hypertension (PH): 1. Pulmonaryartery hypertension (PAH) 1.1. Idiopathic PAH 1.2. Heritable 1.2.1.BMPR2 1.2.2. ALK1, endoglin (with or without hereditary hemorrhagictelangiectasia 1.2.3. Unknown 1.3. Drug- and toxin-induced 1.4.Associated with: 1.4.1. Connective tissue diseases 1.4.2. Humanimmunodeficiency virus (HIV) infection 1.4.3. Portal hypertension 1.4.4.Congenital heart diseases 1.4.5. Schistosomiasis 1.5 Persistentpulmonary hypertension of the newborn 1′. Pulmonary veno-occlusivedisease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH) 2.Pulmonary hypertension owing to left heart disease 2.1. Systolicdysfunction 2.2. Diastolic dysfunction 2.3. Valvular disease 3.Pulmonary hypertension owing to lung disease and/or hypoxemia 3.1.Chronic obstructive pulmonary disease 3.2. Interstitial lung disease3.3. Other pulmonary diseases with mixed restrictive and obstructivepattern 3.4. Sleep-disordered breathing 3.5. Alveolar hypoventilationdisorders 3.6. Chronic exposure to high altitude 3.7. Developmentalabnormalities 4. Chronic thromboembolic pulmonary hypertension (CTEPH)5. Pulmonary hypertension with unclear multifactorial mechanisms 5.1.Hematologic disorders: myeoloproliferative disorders, splenectomy 5.2.Systemic disorders: sarcoidosis, pulmonary Langerhans cellhistiocytosis: lymphangioleiomyomatosis, neurofibromatosis, vasculitis5.3. Metabolic disorders: glycogen storage disease, Gaucher disease,thyroid disorders 5.4. Others: tumoral obstruction, fibrosingmediastinitis, chronic renal failure on dialysis

The invention provides certain bis-acylated hydroxylamine derivativecompounds, methods of using such compounds, and pharmaceuticalcompositions and kits comprising such compounds.

In some embodiments, the invention provides a compound of formula (I)

or a pharmaceutically acceptable salt, hydrate, or solvate thereofwherein:

L is a bond, —SO₂— or —O—;

Y is alkyl, aryl, heteroaryl or benzyl, wherein said alkyl, aryl,heteroaryl and benzyl are substituted with one or more substituentsindependently selected from W;

W is halo, —CN, —NO₂, —COR³, —COOR^(S), —CONR³R⁴, —CH(C(O)R³)₂, —SO₂R³or —COX, wherein X is halo, and R³ and R⁴ are independently alkyl oraryl, or R³ and R⁴ are taken together to form a cycloalkyl orheterocycloalkyl, wherein said cycloalkyl and heterocycloalkyl areunsubstituted or substituted with one or more substituents;

R¹ and R² are independently hydrogen, alkyl, heterocycloalkyl, aryl,benzyl, alkoxy, aryloxy, benzyloxy, —NR⁵R⁶, —N(OR⁵)R⁶, —NR⁵C(O)R⁶ or—O-heterocycloalkyl, wherein said alkyl, heterocycloalkyl, aryl, benzyl,alkoxy, aryloxy, benzyloxy, —N(OR⁵)R⁶, —NR⁵C(O)R⁶ and—O-heterocycloalkyl are unsubstituted or substituted with one or moresubstituents; and

R⁵ and R⁶ are independently alkyl or aryl, where said alkyl and aryl areunsubstituted or substituted with one or more substituents.

In some embodiments, L is a bond, —SO₂— or —O—; Y is alkyl, or aryl,wherein said alkyl and aryl are substituted with one or moresubstituents independently selected from W; W is halo, —CN, —NO₂, —COR³,—COOR^(S), —CONR³R⁴, —CH(C(O)R³)₂, —SO₂R³ or —COX, wherein X is halo,and R³ and R⁴ are independently alkyl or aryl, or R³ and R⁴ are takentogether to form a cycloalkyl or heterocycloalkyl, wherein saidcycloalkyl and heterocycloalkyl are unsubstituted or substituted withone or more substituents; R¹ and R² are independently hydrogen, alkyl,heterocycloalkyl, aryl, benzyl, alkoxy, aryloxy, benzyloxy or —NR⁵R⁶,wherein said alkyl, heterocycloalkyl, aryl, benzyl, alkoxy, aryloxy andbenzyloxy are unsubstituted or substituted with one or moresubstituents; and R⁵ and R⁶ are independently alkyl or aryl.

In some embodiments, when L is —SO₂—, R² is phenyl or alkyl, and Y isphenyl substituted with one substituent selected from W, then W is not4-chloro or 4-nitro; and when L is —SO₂—, R² is alkyl, and Y is phenylsubstituted with two or three substituents independently selected fromW, then two of the substituents are not 3-nitro and 5-nitro.

Included in any of the embodiments disclosed above are the followingadditional embodiments which may be combined in any variation.

In some embodiments, L is —SO₂—.

In some embodiments, Y is aryl substituted with one or more substituentsindependently selected from W.

In some embodiments, Y is aryl substituted with one, two or threesubstituents independently selected from W.

In some embodiments, Y is phenyl substituted with one or moresubstituents independently selected from W.

In some embodiments, Y is heteroaryl, wherein said heteroaryl isunsubstituted or substituted with one or more substituents independentlyselected from W.

In some embodiments, Y is benzyl wherein said benzyl is substituted withone or more substituents independently selected from W.

In some embodiments, W is halo, —SO₂R³ or —NO₂.

In some embodiments, W is chloro, bromo, fluoro or —NO₂.

In some embodiments, R¹ and R² are independently alkyl,heterocycloalkyl, alkoxy, phenyl, benzyl or benzyloxy, wherein saidalkyl, heterocycloalkyl, alkoxy, phenyl, benzyl and benzyloxy areunsubstituted or substituted with one or more substituents independentlyselected from halo, alkyl, nitro, alkylsulfonyl, trihalomethyl, phenyl,—C(O)OR¹¹, —C(O)R¹³, —OC(O)R¹³, —NR¹¹R¹², —NR¹¹C(O)OR¹³ and —OR¹¹.

In some embodiments, R¹ and R² are independently alkyl,heterocycloalkyl, alkoxy, phenyl or benzyloxy, wherein said alkyl,heterocycloalkyl, alkoxy, phenyl, and benzyloxy are unsubstituted orsubstituted with one or more substituents independently selected fromhalo, alkyl, nitro, alkylsulfonyl and trihalomethyl.

In some embodiments, R¹¹ is C₁-C₆ alkyl optionally substituted withalkoxy.

In some embodiments, R¹² is C₁-C₄ alkyl.

In some embodiments, R¹³ is C₁-C₄ alkyl.

In some embodiments, R⁵ and R⁶ are independently C₁-C₆ alkyl, whereinsaid alkyl is unsubstituted or substituted with one or moresubstituents.

In some embodiments, R⁵ and R⁶ are independently C₁-C₆ alkyl, whereinsaid alkyl is unsubstituted or substituted with one or more substituentsindependently selected from alkoxy, heteroaryl and —C(O)OR¹¹.

In some embodiments, R¹ and R² are independently alkyl,heterocycloalkyl, alkoxy, phenyl or benzyloxy, wherein said alkyl,heterocycloalkyl, alkoxy, phenyl and benzyloxy are unsubstituted orsubstituted with one or more substituents independently selected fromhalo, alkyl, nitro, alkylsulfonyl and trihalomethyl.

In some embodiments, R¹ is alkyl, heterocycloalkyl, alkoxy, phenyl orbenzyloxy, wherein said alkyl is unsubstituted or substituted with oneor more halos, and said heterocycloalkyl is unsubstituted or substitutedwith alkyl; and R² is alkyl or aryl.

In some embodiments, Y is alkyl, wherein said alkyl is substituted withone or more substituents independently selected from W.

In some embodiments, Y is alkyl, wherein said alkyl is substituted withone or more halos.

In some embodiments, Y is alkyl, wherein said alkyl is substituted withone or more substituents independently selected from W; and R¹ and R²are independently alkyl, alkoxy, phenyl or benzyloxy, wherein said alkyland phenyl are unsubstituted or substituted with one or moresubstituents.

In some embodiments, Y is alkyl, wherein said alkyl is substituted withone or more substituents independently selected from W; and R¹ and R²are independently alkyl, alkoxy, phenyl or benzyloxy, wherein said alkyland phenyl are unsubstituted or substituted with one or moresubstituents independently selected from halo, nitro, alkylsulfonyl andtrihalomethyl.

In some embodiments, R¹ is alkyl or alkoxy; and R² is alkyl or phenyl,wherein said phenyl is unsubstituted or substituted with one or moresubstituents independently selected from halo, nitro, alkylsulfonyl andtrihalomethyl.

In some embodiments, Y is phenyl substituted with halo and —CONR³R⁴.

In some embodiments, R³ and R⁴ are taken together to form a cycloalkyl.

In some embodiments, R³ and R⁴ are taken together to form a cycloalkylwherein said cycloalkyl is substituted with one or more substituents.

In some embodiments, R³ and R⁴ are taken together to form aheterocycloalkyl.

In some embodiments, R³ and R⁴ are taken together to form aheterocycloalkyl wherein said heterocycloalkyl is substituted with oneor more substituents.

In some embodiments, the invention provides a compound of formula (Ia)

or a pharmaceutically acceptable salt, hydrate, or solvate thereofwherein:

L is a bond, —SO₂— or —O—;

Y is a heteroaryl, wherein said heteroaryl is unsubstituted orsubstituted with one or more substituents independently selected from W;

W is halo, —CN, —NO₂, —COR³, —COOR³, —CONR³R⁴, —CH(C(O)R³)₂, —SO₂R³ or—COX, wherein X is halo, and R³ and R⁴ are independently alkyl or aryl,or R³ and R⁴ are taken together to form a cycloalkyl orheterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl areunsubstituted or substituted with one or more substituents;

R¹ and R² are independently hydrogen, alkyl, heterocycloalkyl, aryl,benzyl, alkoxy, aryloxy, benzyloxy or —NR⁵R⁶, wherein said alkyl,heterocycloalkyl, aryl, benzyl, alkoxy, aryloxy, and benzyloxy areunsubstituted or substituted with one or more substituents independentlyselected from halo, alkyl, nitro, alkylsulfonyl and trihalomethyl; and

R⁵ and R⁶ are independently alkyl or aryl.

In some embodiments, L is —SO₂—.

In some embodiments, Y is unsubstituted heteroaryl.

In some embodiments, Y is heteroaryl substituted with one or moresubstituents independently selected from W.

In some embodiments, Y is thienyl, furyl, pyrrolyl, pyridyl orbenzofuranyl.

In some embodiments, Y is thienyl, furyl, pyrrolyl, pyridyl orbenzofuranyl substituted with one or more substituents independentlyselected from W.

In some embodiments, Y is thienyl substituted with one or moresubstituents independently selected from W.

In some embodiments, Y is benzofuranyl.

In some embodiments, Y is pyridyl.

In some embodiments, W is halo.

In some embodiments, W is chloro or bromo.

In some embodiments, R¹ is alkoxy.

In some embodiments, R² is alkyl.

In some embodiments, the invention provides a compound of formula (II)

or a pharmaceutically acceptable salt, hydrate, or solvate thereofwherein:

W is halo, —OH, —CN, —NO₂, —COR^(S), —COOR^(S), —CONR³R⁴, —CH(C(O)R³)₂,or —COX, wherein X is halo, and R³, R⁴ and R⁵ are independently alkyl oraryl, or R³ and R⁴ are taken together to form a cycloalkyl orheterocycloalkyl, wherein said cycloalkyl and heterocycloalkyl areunsubstituted or substituted with one or more substituents;

R¹ and R² are independently hydrogen, alkyl, heterocycloalkyl, aryl,benzyl, alkoxy, aryloxy, benzyloxy or —NR⁶R⁷, wherein said alkyl,heterocycloalkyl, aryl, benzyl, alkoxy, aryloxy and benzyloxy areunsubstituted or substituted with one or more substituents; and

R⁶ and R⁷ are independently alkyl or aryl.

In some embodiments, when R¹ and R² are each phenyl, then W is not —CN;and when R¹ is phenylethyl and R² is methyl, then W is not chloro.

Included in any of the embodiments disclosed above are the followingadditional embodiments which may be combined in any variation.

In some embodiments, W is chloro.

In some embodiments, W is bromo.

In some embodiments, W is fluoro.

In some embodiments, R¹ and R² are independently alkyl, alkoxy orphenyl, wherein said alkyl and phenyl are unsubstituted or substitutedwith one or more substituents independently selected from halo, nitro,alkylsulfonyl and trihalomethyl.

In some embodiments, W is —CONR³R⁴.

In some embodiments, R³ and R⁴ are taken together to form a cycloalkyl.

In some embodiments, R³ and R⁴ are taken together to form a cycloalkylwherein said cycloalkyl is substituted with one or more substituents.

In some embodiments, R³ and R⁴ are taken together to form aheterocycloalkyl.

In some embodiments, R³ and R⁴ are taken together to form aheterocycloalkyl wherein said heterocycloalkyl is substituted with oneor more substituents.

Representative compounds of formulae (I), (Ia) and (II) include, but arenot limited to, the following compounds (Table 2).

TABLE 2 Representative compounds of formulae (I), (Ia) and (II):Compound No. Name Structure 1 N-chloro-N-benzoyloxy-benzamide

2 N-chloro-N-(4-chlorobenzoyloxy)-4- chlorobenzamide

3 N-chloro-N-(4-nitrobenzoyl)-4- nitrobenzamide

4 N-chloro-N-(4-nitrobenzoyl)- benzamide

5 N-chloro-N-(2,6-difluorobenzoyl)- benzamide

6 N-chloro-N-acetoxy-benzamide

7 N-chloro-N-dichloroacetyloxy- benzamide

8 N-chloro-N-(2,2,2- trifluoroacetoxy)benzamide

9 N-chloro-N-acetyloxy-acetamide

10 N-chloro-N-acetyloxy-tert-butyl- carbamate

11 N-chloro-ethyl-carbonoxy-ethyl- carbamate

12 N-chloro-N-(trimethylacetyloxy)- trimethylacetamide

13 N-chloro-N-(4-nitrobenzyloxy)-tert- butyl-carbamate

14 N-chloro-N-(acetyloxy)- trimethylacetamide

15 N-bromo-N-acetyloxy-acetamide

18 N-(4-chlorobenzenesulfonyl)-N- acetyloxy-acetamide⁴

19 N-(2-bromobenzenesulfonyl)-N- acetyloxy-acetamide

20 N-(2-chlorobenzenesulfonyl)-N- acetyloxy-acetamide

21 N-(2-bromo-4,6-difluoro- benzenesulfonyl)-N-acetyloxy- acetamide

22 N-(2,6-dibromobenzenesulfonyl)-N- acetyloxy-acetamide

23 N-(2,6-dichlorobenzenesulfonyl)-N- acetyloxy-acetamide

24 N-(2,6-difluorobenzenesulfonyl)-N- acetyloxy-acetamide

25 N-(2-nitrobenzenesulfonyl)-N- acetyloxy-acetamide

26 N-(chloromethylsulfonyl)-N- acetyloxy-acetamide

27 no spectral data

28 N-(2,6-dichlorobenzenesulfonyl)-N- acetyloxy-benzamide

29 N-(2,6-dichlorobenzenesulfonyl)-N- acetyloxy-benzyl-carbamate

30 N-(2,6-dichlorobenzenesulfonyl)-N- acetyloxy-dichloroacetamide

31 N-(2,5-dichlorobenzenesulfonyl)-N- acetyloxy-trimethylacetamide

32 N-(2-nitrobenzenesulfonyl)-N- acetyloxy-trimethylacetamide

33 N-(2,6-dichlorobenzenesulfonyl)-N- acetyloxy-trimethylacetamide

36 N-(2-bromobenzenesulfonyl)-N- acetyloxy-tert-butyl-carbamate

37 N-(2,6-dichlorobenzenesulfonyl)-N- acetyloxy-tert-butyl-carbamate

38 N-(2,6-dibromobenzenesulfonyl)-N- acetyloxy-tert-butyl-carbamate

40 N-(2,6-dichlorobenzenesulfonyl)-N-4-nitrobenzoyloxy)-tert-butyl-carbamate

41 tert-butyl (acetyloxy)[(2- bromophenyl)sulfonyl]carbamate

42 tert-butyl (acetyloxy){[(2- (methylsulfonyl)phenyl]sulfonyl}-carbamate

43 tert-butyl (acetyloxy)[(3- bromothiophen-2-yl)sulfonyl]carbamate

44 tert-butyl {[2-(methylsulfonyl)phenyl]-sulfonyl}(propanoyloxy)carbamate

45 tert-butyl [(2-methylpropanoyl)oxy]{[2-(methylsulfonyl)phenyl]sulfonyl}- carbamate

46 tert-butyl [(2,2- dimethylpropanoyl)oxy]-{[2-(methylsulfonyl)phenyl]sulfonyl}- carbamate

47 tert-butyl {[2-(methylsulfonyl)phenyl]-sulfonyl{[(phenylcarbonyl)oxy]- carbamate

48 ethyl (acetyloxy){[2-(methylsulfonyl)- phenyl]sulfonyl}carbamate

49 ethyl (acetyloxy)[(2-bromophenyl)- sulfonyl]carbamate

50 benzyl (acetyloxy){[2-(methylsulfonyl)- phenyl]sulfonyl}carbamate

51 benzyl {[2-(methylsulfonyl)phenyl]- sulfonyl}(propanoyloxy)carbamate

52 N-[(2,2-dimethylpropanoyl)oxy]-4-methyl-N-{[2-(methylsulfonyl)phenyl]- sulfonyl}piperazine-1-carboxamide

53 N-[(tert-butoxy)carbonyl][2-chloro-5-(dimethylcarbamoyl)benzene]sulfonamido 2,2-dimethylpropanoate

54 N-[(tert-butoxy)carbonyl](2- methanesulfonylbenzene)sulfonamido2-(acetyloxy)benzoate

55 N-[(tert-butoxy)carbonyl]1-benzofuran- 2-sulfonamido2,2-dimethylpropanoate

56 N-[(tert-butoxy)carbonyl]1-benzofuran- 2-sulfonamido acetate

57 N-[(tert-butoxy)carbonyl](2- bromobenzene)sulfonamido benzoate

58 N-[(tert-butoxy)carbonyl]3- bromothiophene-2-sulfonamido 2,2-dimethylpropanoate

59 N-[(tert-butoxy)carbonyl]3- chlorothiophene-2-sulfonamido 2,2-dimethylpropanoate

60 N-[(tert-butoxy)carbonyl](2- bromobenzene)sulfonamido 2-methylpropanoate

61 N-[(tert-butoxy)carbonyl](2- bromobenzene)sulfonamido 2,2-dimethylpropanoate

62 N-[(tert-butoxy)carbonyl](2- chlorobenzene)sulfonamido 2,2-dimethylpropanoate

63 N-[(tert-butoxy)carbonyl][2-chloro-5- (dimethylcarbamoyl)benzene]sulfonamidoacetate

64 N-[(tert-butoxy)carbonyl](2- chlorobenzene)sulfonamido 2-methylpropanoate

65 N-[(tert-butoxy)carbonyl](2- bromobenzene)sulfonamido 2-phenylacetate

66 N-[(tert-butoxy)carbonyl](2- bromobenzene)sulfonamido 2-methyl-2-phenylpropanoate

67 N-[(tert-butoxy)carbonyl](2- bromobenzene)sulfonamido 1-phenylcyclopentane-1-carboxylate

68 2-N-[(tert-butoxy)carbonyl](2- bromobenzene)sulfonamido 1-tert-butylpyrrolidine-1,2-dicarboxylate

69 N-[(tert-butoxy)carbonyl](2- bromobenzene)sulfonamido 2-[4-(dimethylamino)phenyl]acetate

70 N-[(tert-butoxy)carbonyl](2- bromobenzene)sulfonamido 1-acetylpyrrolidine-2-carboxylate

71 N-[(tert-butoxy)carbonyl](2- bromobenzene)sulfonamido (2S)-2-phenylpropanoate

72 N-[(tert-butoxy)carbonyl](2- bromobenzene)sulfonamido (2R)-2-phenylpropanoate

73 N-[(tert-butoxy)carbonyl]-5- chlorothiophene-2-sulfonamido 2-methylpropanoate

74 N-[(tert-butoxy)carbonyl]-5- chlorothiophene-2-sulfonamido 2,2-dimethylpropanoate

75 N-[(tert-butoxy)carbonyl](3- methanesulfonylbenzene)sulfonamido2,2-dimethylpropanoate

76 N-[(tert-butoxy)carbonyl](3- methanesulfonylbenzene)sulfonamido2-methylpropanoate

77 N-[(tert-butoxy)carbonyl]pyridine-3- sulfonamido2,2-dimethylpropanoate

78 N-[(tert-butoxy)carbonyl]pyridine-3- sulfonamido 2-methylpropanoate

79 N-[(tert-butoxy)carbonyl](2- methanesulfonylbenzene)sulfonamido(2S)-2-{[(tert butoxy) carbonyl](methyl)amino}-4- methylpentanoate

80 N-[(tert-butoxy)carbonyl](2- methanesulfonylbenzene)sulfonamido(2R)-2-{[(tert-butoxy)carbonyl] (methyl)amino}propanoate

81 N-[(tert-butoxy)carbonyl](2- methanesulfonylbenzene)sulfonamido(2S)-2-{[(tert-butoxy)carbonyl] (methyl)amino}propanoate

82 N-[(tert-butoxy)carbonyl](2- methanesulfonylbenzene)sulfonamido2-{[(tertbutoxy)carbonyl] (methyl)amino}acetate

83 N-[(tert-butoxy)carbonyl](2- methanesulfonylbenzene)sulfonamido(2S)-2-{[(tert-butoxy)carbonyl] (methyl)amino}-3-methylbutanoate

84 N-[(tert-butoxy)carbonyl][(4- chlorophenyl)methane]sulfonamido 2,2-dimethylpropanoate

85 N-[(benzyloxy)carbonyl](2- methanesulfonylbenzene)sulfonamido2,2-dimethylpropanoate

86 N-[(tert-butoxy)carbonyl](2- methanesulfonylbenzene)sulfonamidoN,N-dimethylcarbamate

87 N-[(tert-butoxy)carbonyl](2- bromobenzene)sulfonamido N,N-dimethylcarbamate

88 N-[(tert-butoxy)carbonyl](2- methanesulfonylbenzene)sulfonamidomorpholine-4-carboxylate

89 N-[(tert-butoxy)carbonyl](2- methanesulfonylbenzene)sulfonamido4-acetylpiperazine-1-carboxylate

90 tert-butyl N-{[cyclohexyl(methyl) carbamoyl]oxy}-N-[(2-methanesulfonylbenzene)sulfonyl] carbamate

91 1-N-[(tert-butoxy)carbonyl](2- methanesulfonylbenzene)sulfonamido4-tert-butyl piperazine-1,4- dicarboxylate

92 N-[(tert-butoxy)carbonyl](2- methanesulfonylbenzene)sulfonamidoN-(2-methoxyethyl)carbamate

93 N-[(tert-butoxy)carbonyl](2- methanesulfonylbenzene)sulfonamido N,Ndiethylcarbamate

94 N-[(tert-butoxy)carbonyl](2- methanesulfonylbenzene)sulfonamidoN-methoxy-N-methylcarbamate

95 tert-butyl N-[(2- methanesulfonylbenzene)sulfonyl]-N-{[methyl(pyridin-3- ylmethyl)carbamoyl]oxy}carbamate

96 tert-butyl 2-{[2-(tert-butoxy)-2- oxoethyl][({N-[(tert-butoxy)carbonyl](2- methanesulfonylbenzene)sulfonamido}oxy)carbonyl]amino}acetate

97 4-{[({N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido} oxy)carbonyl]oxy}oxane

98 4-{[({N-[(tert-butoxy)carbonyl](2- bromobenzene)sulfonamido}oxy)carbonyl]oxy}oxane

99 1-({[(tert-butoxy)carbonyl] [(methoxycarbonyl)oxy]amino}sulfonyl)-2-methanesulfonyl benzene

100 1-({[(tert-butoxy)carbonyl]({[(2- methoxyethoxy)carbonyl]oxy})amino}sulfonyl)-2-methanesulfonylbenzene

101 1-({[(tert-butoxy)carbonyl]({[2-(2-methoxyethoxy)ethoxy]carbonyl}oxy) amino}sulfonyl)-2-methanesulfonylbenzene

102 1-({[(tert-butoxy)carbonyl]({[(1,3- diethoxypropan-2-yl)oxy]carbonyl}oxy)amino} sulfonyl)-2-methanesulfonylbenzene

103 tert-butyl (acetyloxy)[(3-bromothiophen-2- yl)sulfonyl]carbamate

104 N-[(tert-butoxy)carbonyl]1-benzofuran-2- sulfonamido2,2-dimethylpropanoate

105 N-[(tert-butoxy)carbonyl]1-benzofuran-2- sulfonamido acetate

106 N-[(tert-butoxy)carbonyl]3- bromothiophene-2-sulfonamido 2,2-dimethylpropanoate

107 N-[(tert-butoxy)carbonyl]3- chlorothiophene-2-sulfonamido 2,2-dimethylpropanoate

108 N-[(tert-butoxy)carbonyl]5 chlorothiophene-2-sulfonamido 2-methylpropanoate

109 N-[(tert-butoxy)carbonyl]5- chlorothiophene-2-sulfonamido 2,2-dimethylpropanoate

110 N-[(tert-butoxy)carbonyl]pyridine-3- sulfonamido2,2-dimethylpropanoate

111 N-[(tert-butoxy)carbonyl]pyridine-3- sulfonamido 2-methylpropanoate

⁴Compound 18 was previously reported by H. T. Nagasawa et al., J. Med.Chem. 1992, 35, 3648-3652.

In some embodiments, the compound is one that donates nitroxyl underphysiological conditions.

For all compounds disclosed herein, where applicable due to the presenceof a stereocenter, the compound is intended to embrace all possiblestereoisomers of the compound depicted or described. Compositionscomprising a compound with at least one stereocenter are also embracedby the invention, and include racemic mixtures or mixtures containing anenantiomeric excess of one enantiomer or single diastereomers ordiastereomeric mixtures. All such isomeric forms of these compounds areexpressly included herein the same as if each and every isomeric formwere specifically and individually listed. The compounds herein may alsocontain linkages (e.g., carbon-carbon bonds) wherein bond rotation isrestricted about that particular linkage, e.g. restriction resultingfrom the presence of a ring or double bond. Accordingly, all cis/transand E/Z isomers are also expressly included in the present invention.The compounds herein may also be represented in multiple tautomericforms, in such instances, the invention expressly includes alltautomeric forms of the compounds described herein, even though only asingle tautomeric form may be represented.

In some embodiments, the invention provides a substantially purecompound. “Substantially pure” intends a preparation of the compoundthat contains no more than 25% of impurity (e.g. by weight %), whichimpurity maybe another compound altogether or a different form of thecompound (e.g. a different salt or isomer). Percent purity may beassessed by methods known in the art. In some embodiments, a preparationof substantially pure compound is provided where the preparationcontains no more than 15% of impurity. In some embodiments, apreparation of substantially pure compound is provided where thepreparation contains no more than 10% impurity. In some embodiments, apreparation of substantially pure compound is provided where thepreparation contains no more than 5% impurity. In some embodiments, apreparation of substantially pure compound is provided where thepreparation contains no more than 3% impurity. In some embodiments, apreparation of substantially pure compound is provided where thepreparation contains no more than 1% impurity.

In some embodiments, the invention provides a compound in purifiedand/or isolated form, for example following column chromatography,high-pressure liquid chromatography, recrystallization, or otherpurification techniques. Where particular stereoisomers of compounds ofthis invention are denoted, such stereoisomers may be substantially freeof other stereoisomers.

Pharmaceutical Compositions

In some embodiments, the invention provides a pharmaceutical compositioncomprising an effective amount of a compound described herein or apharmaceutically acceptable salt thereof, together with apharmaceutically acceptable excipient.

Examples of pharmaceutically acceptable excipients include thosedescribed above, such as carriers, surface active agents, thickening oremulsifying agents, solid binders, dispersion or suspension aids,solubilizers, colorants, flavoring agents, coatings, disintegratingagents, lubricants, sweeteners, preservatives, isotonic agents, andcombinations thereof. The selection and use of pharmaceuticallyacceptable excipients are taught in “Remington: The Science and Practiceof Pharmacy”, 21st Ed. (Lippincott Williams & Wilkins 2005), thedisclosure of which is incorporated herein by reference.

The pharmaceutical compositions may be formulated for administration insolid or liquid form, including those adapted for the following: (1)oral administration, for example, drenches (for example, aqueous ornon-aqueous solutions or suspensions), tablets (for example, thosetargeted for buccal, sublingual and systemic absorption), caplets,boluses, powders, granules, pastes for application to the tongue, hardgelatin capsules, soft gelatin capsules, mouth sprays, troches,lozenges, pellets, syrups, suspensions, elixirs, liquids, emulsions andmicroemulsions; (2) parenteral administration, for example, bysubcutaneous, intramuscular, intravenous or epidural injection as, forexample, a sterile solution or suspension; (3) topical application, forexample, as a cream, ointment, patch, pad or spray applied to the skin;(4) intravaginally or intrarectally, for example, as a pessary, cream orfoam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.The pharmaceutical compositions may be for immediate, sustained orcontrolled release.

In some embodiments, the pharmaceutical compositions are formulated fororal administration. In some embodiments, the pharmaceuticalcompositions are formulated for intravenous administration. In someembodiments, the pharmaceutical compositions are formulated foradministration by inhalation.

The compounds and pharmaceutical compositions described herein may beprepared as any appropriate unit dosage form, such as capsules, sachets,tablets; powder, granules, solution, suspension in an aqueous liquid ora non-aqueous liquid, oil-in-water liquid emulsion, water-in-oil liquidemulsion, liposomes and bolus.

Tablets may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, preservative, surface-active ordispersing agent. Molded tablets may be made by molding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may be optionally coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein. Methods of formulating such slow or controlledrelease compositions of pharmaceutically active ingredients, such asthose herein and other compounds known in the art, are known in the artand described in several issued US patents, some of which include, butare not limited to, U.S. Pat. Nos. 4,369,174 and 4,842,866, andreferences cited therein. Coatings can be used for delivery of compoundsto the intestine (see, e.g. U.S. Pat. Nos. 6,638,534, 5,217,720 and6,569,457, and references cited therein). A skilled artisan willrecognize that in addition to tablets, other dosage forms can beformulated to provide slow or controlled release of the activeingredient. Such dosage forms include, but are not limited to, capsules,granulations and gel-caps.

Pharmaceutical compositions suitable for topical administration include,without limitation, lozenges comprising the ingredients in a flavoredbasis, such as sucrose, acacia and tragacanth; and pastilles comprisingthe active ingredient in a flavored basis or in an inert basis, such asgelatin and glycerin.

Pharmaceutical compositions suitable for parenteral administrationinclude, without limitation, aqueous and non-aqueous sterile injectionsolutions containing, for example, anti-oxidants, buffers, bacteriostatsand solutes that render the formulation isotonic with the blood of theintended recipient; and aqueous and non-aqueous sterile suspensionscontaining, for example, suspending agents and thickening agents. Theformulations may be presented in unit-dose or multi-dose containers, forexample, sealed ampules and vials, and may be stored in a freeze dried(lyophilized) condition requiring only the addition of a sterile liquidcarrier, such as water, immediately prior to use. In some embodiments,the aqueous composition is acidic, having a pH of about 5.5 to about 7.

Extemporaneous injection solutions and suspensions may be prepared fromsterile powders, granules and tablets.

Methods of Using the Compounds and Pharmaceutical Compositions

In some embodiments, the invention provides a method of modulating (suchas increasing or reducing) in vivo nitroxyl levels, comprisingadministering to an individual in need thereof a compound orpharmaceutical composition as described herein. In some embodiments, theindividual has, is suspected of having, or is at risk of having ordeveloping a disease or condition that is responsive to nitroxyltherapy.

In some embodiments, the invention provides a method of treating,preventing or delaying the onset and/or development of a disease orcondition, comprising administering to an individual (including anindividual identified as in need of such treatment, prevention or delay)an effective amount of a compound or pharmaceutical composition asdescribed herein. Identifying an individual in need thereof can be inthe judgment of a physician, clinical staff, emergency responsepersonnel or other health care professional and can be subjective (e.g.opinion) or objective (e.g. measurable by a test or diagnostic method).

Particular diseases or conditions embraced by the methods describedherein include, without limitation, cardiovascular diseases, ischemia,reperfusion injury, cancerous diseases, pulmonary hypertension andconditions responsive to nitroxyl therapy.

Cardiovascular Diseases

In some embodiments, the invention provides a method of treating acardiovascular disease, comprising administering an effective amount ofa compound or pharmaceutical composition as described herein to anindividual in need thereof.

Examples of cardiovascular diseases include, without limitation,cardiovascular diseases that are responsive to nitroxyl therapy,coronary obstructions, coronary artery disease (CAD), angina, heartattack, myocardial infarction, high blood pressure, ischemiccardiomyopathy and infarction, pulmonary congestion, pulmonary edema,cardiac fibrosis, valvular heart disease, pericardial disease,circulatory congestive states, peripheral edema, ascites, Chagas'disease, ventricular hypertrophy, heart valve disease, heart failure,diastolic heart failure, congestive heart failure, acute congestiveheart failure, acute decompensated heart failure, and cardiachypertrophy.

In some embodiments, the individual is experiencing heart failure. Insome embodiments, the individual is experiencing heart failure and/orundergoing treatment with a positive inotrope. In some embodiments, theindividual is experiencing heart failure and/or undergoing treatmentwith a beta-andrenergic receptor antagonist (also referred to herein asbeta-antagonist or beta-blocker). A beta-antagonist includes anycompound that effectively acts as an antagonist at an individual'sbeta-adrenergic receptors, and provides desired therapeutic orpharmaceutical results, such as diminished vascular tone and/or heartrate. An individual that is undergoing treatment with a beta-antagonistis any individual to whom a beta-antagonists has been administered, andin whom the beta-antagonist continues to act as an antagonist at theindividual's beta-adrenergic receptors. Examples of beta-antagonistsinclude, without limitation, propranolol, metoprolol, bisoprolol,bucindolol, and carvedilol.

In some embodiments, the individual is experiencing heart failure and/orundergoing treatment with a beta-adrenergic receptor agonist (alsoreferred to herein as beta-agonist). Examples of beta-agonists include,without limitation, dopamine, dobutamine, isoproterenol, and analogs andderivatives of such compounds.

The determination of whether an individual is undergoing treatment witha positive inotrope, beta-antagonist or beta-agonist may be made byexamination of the individual's medical history, or screening of theindividual for the presence of such agents by chemical tests, such ashigh-speed liquid chromatography, as described in Thevis et al., Biomed.Chromatogr. 2001, 15, 393-402.

In some embodiments, the method further comprises administering aneffective amount of at least one other positive inotrope to theindividual. In some embodiments, the method further comprisesadministering an effective amount of a beta-antagonist to theindividual. In some embodiments, the method further comprisesadministering an effective amount of a beta-agonist to the individual.

In some embodiments, the cardiovascular disease is heart failure. Theheart failure may be of any type or form, including any of the heartfailures described herein. Nonlimiting examples of heart failure includeearly stage heart failure, Class I, II, III or IV heart failure, acuteheart failure, congestive heart failure (CHF) and acute congestive heartfailure.

In some embodiments, the cardiovascular disease is CHF, and the methodfurther comprises administering an effective amount of at least oneother positive inotropic agent to the individual. In some embodiments,the individual is experiencing heart failure. In some embodiments, theat least one other positive inotrope is a beta-adrenergic agonist. Insome embodiments, the beta-adrenergic agonist is dobutamine.

Ischemia or Reperfusion Injury

In some embodiments, the invention provides a method of treating,preventing or delaying the onset and/or development of ischemia orreperfusion injury, comprising administering an effective amount of acompound or pharmaceutical composition as described herein to a subjectin need thereof.

In some embodiments, the method is for preventing ischemia orreperfusion injury. In some embodiments, the compound or pharmaceuticalcomposition is administered prior to the onset of ischemia. In someembodiments, the pharmaceutical composition is administered prior toprocedures in which myocardial ischemia may occur, for example anangioplasty or surgery, such as a coronary artery bypass graft surgery.In some embodiments, the compound or pharmaceutical composition isadministered after ischemia but before reperfusion. In some embodiments,the compound or pharmaceutical composition is administered afterischemia and reperfusion.

In some embodiments, the subject is an individual. In some embodiments,the subject is an individual at risk for an ischemic event. In someembodiments, the individual is at risk for a future ischemic event, buthas no present evidence of ischemia. The determination of whether anindividual is at risk for an ischemic event can be performed by anymethod known in the art, such as examining the individual or theindividual's medical history. In some embodiments, the individual hashad a prior ischemic event. Thus, the individual may be at risk of afirst or subsequent ischemic event. Examples of individuals at risk foran ischemic event include individuals with known hypercholesterolemia,EKG changes associated with ischemia (e.g., peaked or inverted T-wavesor ST segment elevations or depression in an appropriate clinicalcontext), abnormal EKG not associated with active ischemia, elevatedCKMB, clinical evidence of ischemia (e.g., crushing sub-sternal chestpain or arm pain, shortness of breath and/or diaphoresis), prior historyof myocardial infarction, elevated serum cholesterol, sedentarylifestyle, angiographic evidence of partial coronary artery obstruction,echocardiographic evidence of myocardial damage, or any other evidenceof a risk for a future ischemic event. Examples of ischemic eventsinclude, without limitation, myocardial infarction (MI) andneurovascular ischemia, such as a cerebrovascular accident CVA).

In some embodiments, the subject is an organ that is to be transplanted.In some embodiments, the compound or pharmaceutical composition isadministered prior to reperfusion of the organ in a transplantrecipient. In some embodiments, the compound or pharmaceuticalcomposition is administered prior to removal of the organ from thedonor, for example through the perfusion cannulas used in the organremoval process. If the organ donor is a live donor, for example akidney donor, the compound or pharmaceutical composition can beadministered to the organ donor. In some embodiments, the compound orpharmaceutical composition is administered by storing the organ in asolution comprising the compound or pharmaceutical composition. Forexample, the compound or pharmaceutical composition can be included inthe organ preservation solution, such as the University of Wisconsin“UW” solution, which is a solution comprising hydroxyethyl starchsubstantially free of ethylene glycol, ethylene chlorohydrin and acetone(see, U.S. Pat. No. 4,798,824). In some embodiments, the amount of thecompound or pharmaceutical composition is such that ischemia orreperfusion injury to the tissues of the organ is reduced uponreperfusion in the recipient of transplanted organ. In some embodiments,the method reduces tissue necrosis (the size of infarct) in at-risktissues.

Ischemia or reperfusion injury may damage tissues other than those ofthe myocardium and the invention embraces methods of treating orpreventing such damage. In some embodiments, the ischemia or reperfusioninjury is non-myocardial. In some embodiments, the method reduces injuryfrom ischemia or reperfusion in the tissue of the brain, liver, gut,kidney, bowel, or any part of the body other than the myocardium. Insome embodiments, the individual is at risk for such injury. Selecting aperson at risk for non-myocardial ischemia could include a determinationof the indicators used to assess risk for myocardial ischemia. However,other factors may indicate a risk for ischemia/reperfusion in othertissues. For example, surgery patients often experience surgery relatedischemia. Thus, individuals scheduled for surgery could be considered atrisk for an ischemic event. The following risk factors for stroke (or asubset of these risk factors) could demonstrate an individual's risk forischemia of brain tissue: hypertension, cigarette smoking, carotidartery stenosis, physical inactivity, diabetes mellitus, hyperlipidemia,transient ischemic attack, atrial fibrillation, coronary artery disease,congestive heart failure, past myocardial infarction, left ventriculardysfunction with mural thrombus, and mitral stenosis. Ingall, Postgrad.Med. 2000, 107(6), 34-50. Further, complications of untreated infectiousdiarrhea in the elderly can include myocardial, renal, cerebrovascularand intestinal ischemia. Slotwiner-Nie et al., Gastroenterol. Clin. N.Am. 2001, 30(3), 625-635. Alternatively, individuals could be selectedbased on risk factors for ischemic bowel, kidney or liver disease. Forexample, treatment would be initiated in elderly individuals at risk ofhypotensive episodes (such as surgical blood loss). Thus, individualspresenting with such an indication would be considered at risk for anischemic event. In some embodiments, the individual has any one or moreof the conditions listed herein, such as diabetes mellitus orhypertension. Other conditions that may result in ischemia, such ascerebral arteriovenous malformation, could demonstrate an individual'srisk for an ischemic event.

In some embodiments, the method further comprises administering anadditional therapeutic agent. The therapeutic agent may be, for example,a nitroxyl-donating compound, such as Angeli's salt or another compounddescribed herein, a beta-blocker, a calcium channel blocker, ananti-platelet agent or any other therapeutic agent for reducing ischemicinjury or for protecting myocardium in the individual.

Cancerous Diseases

In some embodiments, the invention provides a method of treating,preventing or delaying the onset and/or development of a cancerousdisease, comprising administering an effective amount of a compound orpharmaceutical composition as described herein to an individual in needthereof.

In some embodiments, the individual has or is suspected of having acancerous disease, e.g. cancer.

Cancers that may be treated by the methods described herein include,without limitation, cancers of the head and neck, which include tumorsof the head, neck, nasal cavity, paranasal sinuses, nasopharynx, oralcavity, oropharynx, larynx, hypopharynx, salivary glands, andparagangliomas; cancers of the liver and biliary tree, such ashepatocellular carcinoma; intestinal cancers, such as colorectal cancer;ovarian cancer; small cell and non-small cell lung cancer; breast cancersarcomas, such as fibrosarcoma, malignant fibrous histiocytoma,embryonal rhabdomysocarcoma, leiomysosarcoma, neurofibrosarcoma,osteosarcoma, synovial sarcoma, liposarcoma, and alveolar soft partsarcoma; neoplasms of the central nervous systems, such as brain cancer;lymphomas such as Hodgkin's lymphoma, lymphoplasmacytoid lymphoma,follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantlecell lymphoma, B-lineage large cell lymphoma, Burkitt's lymphoma, andT-cell anaplastic large cell lymphoma.

In some embodiments, the method further comprises administering aneffective amount of an additional therapeutic agent to the individual.In some embodiments, the additional therapeutic agent is an anti-canceragent or a cytotoxic agent. Examples of such agents include, withoutlimitation, alkylating agents, angiogenesis inhibitors,anti-metabolites, DNA cleavers, DNA crosslinkers, DNA intercalators, DNAminor groove binders, enediynes, heat shock protein 90 inhibitors,histone deacetylase inhibitors, microtubule stabilizers, nucleoside(purine or pyrimidine) analogs, nuclear export inhibitors, proteasomeinhibitors, topoisomerase (I or II) inhibitors, tyrosine kinaseinhibitors. Specific anti-cancer or cytotoxic agents include, forexample, beta.-lapachone, ansamitocin P3, auristatin, bicalutamide,bleomycin, bleomycin, bortezomib, busulfan, calicheamycin, callistatinA, camptothecin, capecitabine, cisplatin, cryptophycins, daunorubicin,docetaxel, doxorubicin, duocarmycin, dynemycin A, etoposide,floxuridine, floxuridine, fludarabine, fluoruracil, gefitinib,gemcitabine, hydroxyurea, imatinib, interferons, interleukins,irinotecan, methotrexate, mitomycin C, oxaliplatin, paclitaxel,spongistatins, suberoylanilide hydroxamic acid (SAHA), thiotepa,topotecan, trichostatin A, vinblastine, vincristine and vindesine.

Pulmonary Hypertension

In some embodiments, the invention provides a method of treating,preventing or delaying the onset and/or development of pulmonaryhypertension, comprising administering an effective amount of a compoundor pharmaceutical composition as described herein to an individual inneed thereof. In some embodiments, the pulmonary hypertension isselected from the diseases and conditions listed above in Table 1. Insome embodiments, the pulmonary hypertension is pulmonary arterialhypertension (PAH). In some embodiments, the pulmonary hypertension ispulmonary hypertension owing to left heart disease. In some embodiments,the left heart disease is left heart failure. In some embodiments, theleft heart failure is systolic heart failure. In some embodiments, theleft heart failure is diastolic heart failure. In some embodiments, theleft heart failure is chronic or acutely decompensated. In someembodiments, the pulmonary hypertension is chronic thromboembolicpulmonary hypertension.

In some embodiments, the invention provides a method of reducing meanpulmonary arterial pressure (MPAP), comprising administering aneffective amount of a compound or a pharmaceutical composition describedherein to an individual in need thereof. In some embodiments, the MPAPis reduced by up to about 50%. In some embodiments, the MPAP is reducedby up to about 25%. In some embodiments, the MPAP is reduced by up to20%. In some embodiments, the MPAP is reduced by up to 15%. In someembodiments, the MPAP is reduced by up to 10%. In some embodiments, theMPAP is reduced by up to 5%. In some embodiments, the MPAP is reduced toabout 12 to 16 mmHg. In some embodiments, the MPAP is reduced to about15 mmHg.

Administration Modes, Regimens and Dose Levels

Any administration regimen well known to those skilled in the art forregulating the timing and sequence of drug delivery can be used andrepeated as necessary to effect treatment in the methods describedherein. For example, the compound or pharmaceutical composition may beadministered 1, 2, 3 or 4 times daily, by a single dose, multiplediscrete doses or continuous infusion.

The compound or pharmaceutical composition may be administered prior to,at substantially the same time with, or after administration of anadditional therapeutic agent. The administration regimen may includepretreatment and/or co-administration with the additional therapeuticagent. In such case, the compound or pharmaceutical composition and theadditional therapeutic agent may be administered simultaneously,separately, or sequentially.

Examples of administration regimens include without limitation:

administration of each compound, pharmaceutical composition andtherapeutic agent in a sequential manner; and

co-administration of each compound, pharmaceutical composition andtherapeutic agent in a substantially simultaneous manner (e.g., as in asingle unit dosage form) or in multiple, separate unit dosage forms foreach compound, pharmaceutical composition and therapeutic agent.

Administration of the compound or pharmaceutical composition may be viaany accepted mode known to one skilled in the art, for example, orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally, intraocularly, intrapulmonarily, or via animplanted reservoir. The term “parenterally” includes without limitationsubcutaneously, intravenously, intramuscularly, intraperitoneally,intrathecally, intraventricularly, intrasternally, intracranially, byintraosseous injection and by infusion techniques. Administration mayinvolve systemic exposure or may be local, such as when a compound orpharmaceutical composition is administered at the site of interest.Various tools can be used for administering at the site of interest,such as catheters, trocars, projectiles, pluronic gels, stems, sustaineddrug release polymers or other devices which provide for internalaccess. Where the compound or pharmaceutical composition is administeredto an organ to be donated, such organ may be bathed in a mediumcontaining the compound or pharmaceutical composition. Alternatively,the compound or pharmaceutical composition may be painted onto theorgan, or may be applied in any suitable manner.

It will be appreciated by those skilled in the art that the “effectiveamount” or “dose level” will depend on various factors such as theparticular administration mode, administration regimen, compound, andcomposition selected, and the particular disease and patient beingtreated. For example, the appropriate dose level may vary depending uponthe activity, rate of excretion and possible toxicity of the specificcompound or composition employed; the age, body weight, general health,gender and diet of the patient being treated; the frequency ofadministration; the other therapeutic agent(s) being co-administered;and the type and severity of the disease.

The compounds and pharmaceutical compositions described herein may beadministered at suitable dose level. In some embodiments, the compoundor pharmaceutical composition is administered at a dose level of about0.0001 to 4.0 grams once per day (or multiple doses per day in divideddoses) for adults. Thus, in some embodiments, the compound orpharmaceutical composition is administered at a dose level range inwhich the low end of the range is any amount between 0.1 mg/day and 400mg/day and the high end of the range is any amount between 1 mg/day and4000 mg/day (e.g., 5 mg/day and 100 mg/day, 150 mg/day and 500 mg/day).In some embodiments, the compound or pharmaceutical composition isadministered at a dose level range in which the low end of the range isany amount between 0.1 mg/kg/day and 90 mg/kg/day and the high end ofthe range is any amount between 1 mg/kg/day and 100 mg/kg/day (e.g., 0.5mg/kg/day and 2 mg/kg/day, 5 mg/kg/day and 20 mg/kg/day).

In some embodiments, the compound or pharmaceutical composition isadministered at a weight base dose. In some embodiments, the dose levelis about 0.001 to about 10,000 mg/kg/d. In some embodiments, the doselevel is about 0.01 to about 1,000 mg/kg/d. In some embodiments, thedose level is about 0.01 to about 100 mg/kg/d. In some embodiments, thedose level is about 0.01 to about 10 mg/kg/d. In some embodiments, thedose level is about 0.1 to about 1 mg/kg/d. In some embodiments, thedose level is less than about 1 g/kg/d.

The dose level can be adjusted for intravenous administration. In suchcase, the compound or pharmaceutical composition can be administered inan amount of between about 0.01 μg/kg/min to about 100 μg/kg/min, about0.05 μg/kg/min to about 95 μg/kg/min, about 0.1 μg/kg/min to about 90μg/kg/min, about 1.0 μg/kg/min to about 80 μg/kg/min, about 10.0μg/kg/min to about 70 μg/kg/min, about 20 μg/kg/min to about 60μg/kg/min, about 30 μg/kg/min to about 50 μg/kg/min, about 0.01μg/kg/min to about 1.0 μg/kg/min, about 0.01 μg/kg/min to about 10μg/kg/min, about 0.1 μg/kg/min to about 1.0 μg/kg/min, about 0.1μg/kg/min to about 10 μg/kg/min, about 1.0 μg/kg/min to about 5μg/kg/min, about 70 μg/kg/min to about 100 μg/kg/min, about 80 μg/kg/minto about 90 μg/kg/min.

The dosing interval can be adjusted according to the needs of theindividual. For longer intervals of administration, extended release ordepot formulations can be used.

Kits Comprising the Compounds or Pharmaceutical Compositions

In some embodiments, the invention provides a kit comprising a compoundor a pharmaceutical composition described herein.

In some embodiments, the kit further comprises instructions for usingthe compound or pharmaceutical composition. The instructions may be inany appropriate form, such as written or electronic form. In someembodiments, the instructions may be written instructions. In someembodiments, the instructions are contained in an electronic storagemedium (e.g., magnetic diskette or optical disk). In some embodiments,the instructions include information as to the compound orpharmaceutical composition and the manner of administering the compoundor pharmaceutical composition to an individual. In some embodiments, theinstructions relate to a method of use described herein (e.g., treating,preventing and/or delaying onset and/or development of a disease orcondition selected from cardiovascular diseases, ischemia, reperfusioninjury, cancerous disease, pulmonary hypertension and conditionsresponsive to nitroxyl therapy).

In some embodiments, the kit further comprises suitable packaging. Wherethe kit comprises more than one compound or pharmaceutical composition,the compounds or pharmaceutical compositions may be packagedindividually in separate containers, or combined in one container wherecross-reactivity and shelf life permit.

Other than in the working examples, or where otherwise indicated, allnumbers expressing quantities of ingredients, reaction conditions, andso forth used in the specification and claims are to be understood asbeing modified by the term “about”. Accordingly, unless indicated to thecontrary, such numbers are approximations that may vary depending uponthe-desired properties sought to be obtained by the present invention.At the very least, and not as an attempt to limit the application of thedoctrine of equivalents to the scope of the claims, each numericalparameter should be construed in light of the number of significantdigits and ordinary rounding techniques.

While the numerical ranges and parameters setting forth the broad scopeof the invention are approximations, the numerical values set forth inthe working examples are reported as precisely as possible. Anynumerical value, however, inherently contains certain errors necessarilyresulting from the standard deviation found in their respective testingmeasurements.

EXAMPLES

The following examples are presented for illustrative purposes andshould not serve to limit the scope of the invention.

General Synthetic Methods

All NMR are recorded on one of the following instruments; Bruker AVANCE400 MHz spectrometer, Bruker 250, 360 or 500 operating at ambient probetemperature using an internal deuterium lock. Chemical shifts arereported in parts per million (ppm) at lower frequency relative totetramethylsilane (TMS). Standard abbreviations are used throughout (s:singlet; br. s: broad singlet; d: doublet; dd: doublet of doublets; t:triplet; q: quartet; quin: quintet; m: multiplet). Coupling constantsare reported in Hertz (Hz).

Example 1 Synthesis of Compounds 1-15

N-Halo-N-acyloxy-amides (1-15). N,O-bis-acylated hydroxylamines aresynthesized by known literature methods. The N,O-bis-acylatedhydroxylamine is dissolved in dichloromethane and 0.5 equivalents(equiv) of trihaloisocyanuric acid is added in the dark. Upon completionof the reaction (as indicated by TLC), the solution is filtered throughcelite. The filtrate is evaporated under reduced pressure at roomtemperature to give the desired products in typically 90-100% yield.

N-Chloro-N-benzoyloxy-benzamide (1). ¹H NMR (400 MHz, δ) 7.39 (4H, m),7.49 (1H, m), 7.59 (1H, m), 7.79 (2H, d), 7.89 (12H, d); ¹³C NMR (100MHz, δ) 125.98, 128.58, 128.90, 129.35, 129.94, 130.02, 133.23, 134.83,163.36, 173.51; IR (KBr, cm⁻¹) 1730.0, 1770.2.

N-Chloro-N-(4-chlorobenzoyloxy)-4-chlorobenzamide (2). ¹H NMR (400 MHz,δ) 7.38 (2H, d), 7.40 (2H, d), 7.73 (2H, d), 7.86 (2H, d); IR (KBr,cm⁻¹) 1733.1, 1770.0.

N-Chloro-N-(4-nitrobenzoyl)-4-nitrobenzamide (3). ¹H NMR (400 MHz, δ)7.99 (2H, d), 8.16 (2H, d), 8.30 (4H, m); IR (KBr, cm⁻¹) 1732.8, 1770.0.

N-Chloro-N-(4-nitrobenzoyl)-benzamide (4). ¹H NMR (400 MHz, δ) 7.34 (2H,m), 7.47 (1H, m), 7.71 (2H, d), 8.03 (2H, d), 8.19 (2H, d).

N-Chloro-N-(2,6-difluorobenzoyl)-benzamide (5). ¹H NMR (400 MHz, δ) 6.91(2H, t) 7.40 (2H, m), 7.46 (1H, t), 7.52 (1H, t), 7.77 (2H, d).

N-Chloro-N-acetoxy-benzamide (6). ¹H NMR (400 MHz, δ) 1.99 (1H, s), 7.41(2H, m), 7.54 (1H, m), 7.71 (2H, d); IR (KBr, cm⁻¹) 1722.2, 1804.1.

N-Chloro-N-dichloroacetyloxy-benzamide (7). ¹H NMR (400 MHz, δ) 7.48(2H, m), 7.60 (1H, m), 7.78 (2H, d); IR (KBr, cm⁻¹) 1736.0, 1811.9.

N-Chloro-N-acetyloxy-acetamide (9). ¹H NMR (400 MHz, δ) 2.13 (3H, s),2.17 (3H, s); IR (KBr, cm⁻¹) 1732.9, 1805.1.

N-Chloro-N-acetyloxy-tert-butyl-carbamate (10). ¹H NMR (400 MHz, δ) 1.51(9H, s), 2.16 (3H, s); ¹³C NMR (100 MHz, δ) 18.49, 27.59, 86.76, 155.63,167.32; IR (KBr, cm⁻¹) 1764.6, 1804.4.

N-Chloro-N-ethyl-carbonoxy-ethyl-carbamate (11). ¹H NMR (400 MHz, δ)1.37 (6H, q), 4.37 (4H, t); IR (KBr, cm⁻¹) 1772.6, 1799.9.

N-Chloro-N-(trimethylacetyloxy)-trimethylacetamide (12). ¹H NMR (400MHz, δ) 1.26 (9H, s), 1.28 (9H, s).

N-Chloro-N-(4-nitrobenzoyloxy)-tert-butyl-carbamate (13). ¹H NMR (400MHz, δ) 1.53 (9H, s), 8.24 (2H, d), 8.32 (2H, d); ¹³C NMR (100 MHz, δ)27.60, 87.53, 123.92, 131.26, 132.07, 151.28, 155.41, 161.74; IR (KBr,cm⁻¹) 1753.7, 1780.0.

N-Chloro-N-(acetyloxy)-trimethylacetamide (14). ¹H NMR (400 MHz, δ) 1.27(9H, s), 2.21 (3H, s); ¹³C NMR (100 MHz, δ) 18.72, 27.48, 41.26, 166.26,181.47; IR (KBr, cm⁻¹) 1731.3, 1811.0.

N-Bromo-N-acetyloxy-acetamide (15). ¹H NMR (400 MHz, δ) 2.21 (3H, s),2.26 (3H, s); ¹³C NMR (100 MHz, δ) IR (KBr, cm⁻¹) 1702.7, 1798.0.

Example 2 Synthesis of Compounds 18-33

N-Sulfonyl-N-acyloxy-amides (18-33). ToN-sulfonyl-N-acyloxy-tert-butyl-carbamate (see protocol for 36-40below), 5 equivalents trifluoroacetic acid are added and the mixture isstirred for five minutes. The mixture is washed several times withhexane. The resultant N-acyloxy-sulfonamide is purified by columnchromatography. To a solution of the N-acyloxy-sulfonamide stirring intetrahydrofuran, 1.1 equivalents of triethylamine is added. After fiveminutes, 1.1 equivalents of an appropriate acid chloride is added andthe solution is stirred until completion of the reaction (as indicatedby TLC). The solvent is removed under reduced pressure and the crudeproduct is purified by column chromatography.

N-(4-Chlorobenzenesulfonyl)-N-acetyloxy-acetamide (18)⁵. ¹H NMR (400MHz, δ) 2.19 (3H, s), 2.30 (3H, s), 7.54 (2H, d), 7.97 (2H, d); ¹³C NMR(100 MHz, δ) 17.99, 22.60, 129.57, 130.73, 135.65, 141.78, 167.19,167.68; IR (KBr, cm⁻¹) 1723.5, 1811.9. ⁵ Compound 18 was previouslyreported by H. T. Nagasawa et al., J. Med. Chem. 1992, 35, 3648-3652.

N-(2-Bromobenzenesulfonyl)-N-acetyloxy-acetamide (19). ¹H NMR (400 MHz,δ) 2.20 (3H, s), 2.41 (3H, s), 7.51 (2H, m), 7.76 (1H, m), 8.22 (1H, m);¹³C NMR (100 MHz, δ) 17.84, 23.48, 121.01, 127.97, 133.62, 135.53,136.03, 136.50, 166.45, 166.56; IR (KBr, cm⁻¹) 1723.3, 1811.9; FAB-MS335.95413 (M+H) (335.95347 cal.).

N-(2-Chlorobenzenesulfonyl)-N-acetyloxy-acetamide (20). ¹H NMR (400 MHz,δ) 2.18 (3H, s), 2.37 (3H, s), 7.46 (1H, t), 7.56 (2H, m), 8.16 (1H, d);¹³C NMR (100 MHz, δ): 17.69, 23.24, 127.38, 132.36, 132.89, 133.13,134.64, 135.64, 166.38, 166.53; IR (KBr, cm⁻¹) 1722.2, 1816.2; FAB-MS292.00380 (M+H³⁵Cl) (292.00465), 294.00236 (M+H³⁷Cl) (294.00 170 cal.).

N-(2-Bromo-4,6-difluoro-benzenesulfonyl)-N-acetyloxy-acetamide (21). ¹HNMR (400 MHz, δ) 2.26 (3H, s), 2.47 (3H, s), 7.00 (1H, dd), 7.41 (1H,d); IR (KBr, cm⁻¹) 1728.9, 1815.9; FAB-MS 371.93531 (M+H⁷⁹Br) (371.93529cal.).

N-(2,6-Dibromobenzenesulfonyl)-N-acetyloxy-acetamide (22). ¹H NMR (400MHz, 6) 2.24 (3H, s), 2.45 (3H, s), 7.26 (1H, t), 2.81 (2H, d); ¹³C NMR(100 MHz, δ) 17.75, 23.46, 124.45, 134.76, 134.85, 136.48, 166.04,166.27; IR (KBr, cm⁻¹) 1722.6, 1813.6; FAB-MS 413.86393 (M+H 2x⁷⁹Br)(413.86464 cal.).

N-(2,6-Dichlorobenzenesulfonyl)-N-acetyloxy-acetamide (23). ¹H NMR (400MHz, δ) 2.24 (3H, s), 2.44 (3H, s), 7.45 (1H, t), 7.52 (2H, d); ¹³C NMR(100 MHz, δ) 17.77, 23.41, 131.55, 132.30, 134.45, 136.93; IR (KBr,cm⁻¹) 1718.8, 1813.6; FAB-MS 325.96597 (M+H ³⁵Cl) (325.96567 cal.).

N-(2,6-Difluorobenzenesulfonyl)-N-acetyloxy-acetamide (24). ¹H NMR (400MHz, δ) 2.23 (3H, s), 2.43 (3H, s), 7.10 (2H, m), 7.67 (1H, m); ¹³C NMR(100 MHz, δ) 17.60, 23.05, 113.5 (multiple F coupling), 137.24, 158.72,161.32, 166.18, 166.34; IR (KBr, cm⁻¹) 1738.7, 1809.5; FAB-MS 294.02434(M+H) (294.02478).

N-(2-Nitrobenzenesulfonyl)-N-acetyloxy-acetamide (25). ¹H NMR (400 MHz,δ) 2.29 (3H, s), 2.32 (3H, s), 7.78 (3H, m), 8.30 (1H, d); ¹³C NMR (100MHz, δ) 17.74, 22.72, 124.84, 130.31, 132.29, 133.63, 135.81, 148.10,166.86, 167.16; IR (KBr, cm⁻¹) 1728.8, 1813.5; FAB-MS 303.02861 (M+H)(303.02870 cal.).

N-(Chloromethylsulfonyl)-N-acetyloxy-acetamide (26). ¹H NMR (400 MHz, δ)2.23 (3H, s), 2.26 (3H, s), 4.91 (2H, d); ¹³C NMR (100 MHz, δ) 17.56,22.15, 56.49, 167.17, 168.27; IR (KBr, cm⁻¹) 1734.8, 1818.5.

N-(2,6-Dichlorobenzenesulfonyl)-N-acetyloxy-benzamide (28). ¹H NMR (400MHz, δ) 2.19 (3H, s), 7.47 (6H, m), 7.78 (2H, d); IR (KBr, cm⁻¹) 1719.3,1813.5; FAB-MS 387.98177 (M+H 2x³⁵Cl) (387.98132 cal.).

N-(2,6-Dichlorobenzenesulfonyl)-N-acetyloxy-benzyl-carbamate (29). ¹HNMR (400 MHz, δ) 2.22 (1H, s), 2.32 (2H, s), 5.23 (2H, s), 7.20-7.45(8H, m); IR (KBr, cm⁻¹) 1762.4, 1815.4.

N-(2,6-Dichlorobenzenesulfonyl)-N-acetyloxy-dichloroacetamide (30). ¹HNMR (400 MHz, δ) 2.24 (3H, s), 6.65 (1H, s), 7.49 (3H, m); ¹³C NMR (100MHz, δ) 17.58, 64.10, 132.19, 135.48, 136.91, 160.43, 165.88, 168.39; IR(KBr, cm⁻¹) 1732.9, 1825.5; FAB-MS 393.88707 (M+H) (393.8873).

N-(2,5-Dichlorobenzenesulfonyl)-N-acetyloxy-trimethylacetamide (31). ¹HNMR (400 MHz, δ) 1.30 (9H, s), 2.37 (3H, s), 7.51 (2H, d), 7.55 (2H, d),8.20 (1H, s); ¹³C NMR (100 MHz, δ) 23.02, 26.62, 38.39, 131.17, 133.00,133.33, 133.41, 135.34, 136.12, 166.55, 173.84; IR (KBr, cm⁻¹) 1717.2,1796.2; FAB-MS 368.01253 (M+H 2x³⁵Cl) (368.01263 cal.).

N-(2-Nitrobenzenesulfonyl)-N-acetyloxy-trimethylacetamide (32). ¹H NMR(400 MHz, δ) 1.25 (9H, s), 2.25 (3H, s), 7.65-7.80 (3H, m), 8.25 (1H,d); IR (KBr, cm⁻¹) 1728.6, 1798.4.

N-(2,6-Dichlorobenzenesulfonyl)-N-acetyloxy-trimethylacetamide (33). ¹HNMR (400 MHz, δ) 1.19 (9H, s), 2.39 (3H, s), 7.39 (1H, m), 7.50 (2H, d);IR (KBr, cm⁻¹) 1692.4, 1812.1.

Example 3 Synthesis of Compounds 36-40

N-Sulfonyl-N-acyloxy-tert-butyl-carbamates (36-40).N-Acyloxy-tert-butyl-carbamate is dissolved in anhydrous tetrahydrofuranand 1.05 equivalents of sodium hydride is added. The solution is stirredfor five minutes until gas evolution is complete. To this solution 0.95equivalents of an appropriate sulfonyl chloride is added and stirreduntil the reaction is complete (as indicated by TLC). The solvent isremoved under reduced pressure and the crude product is purified bycolumn chromatography.

N-(2-Bromobenzenesulfonyl)-N-acetyloxy-tert-butyl-carbamate (36). ¹H NMR(400 MHz, δ) 1.38 (9H, s), 2.33 (3H, s), 7.52 (2H, m), 7.80 (1H, d),8.27 (1H, d).

N-(2,6-Dichlorobenzenesulfonyl)-N-acetyloxy-tert-butyl-carbamate (37).¹H NMR (400 MHz, δ) 1.37 (9H, s), 2.29 (3H, s), 7.44-7.51 (3H, m); ¹³CNMR (100 MHz, δ) 17.60, 27.73, 86.91, 131.61, 133.81, 134.25, 136.44,147.89, 167.20; IR (KBr, cm⁻¹) 1766.6, 1815.5.

N-(2,6-Dibromobenzenesulfonyl)-N-acetyloxy-tert-butyl-carbamate (38). ¹HNMR (400 MHz, δ) 1.28 (9H, s), 2.21 (3H, s), 7.21 (1H, t), 7.74 (2H, d);¹³C NMR (100 MHz, δ) 17.94, 27.37, 86.79, 123.73, 134.51, 136.24,136.37, 147.68, 167.19; IR (KBr, cm⁻¹) 1762.4, 1813.1; FAB-MS 473.90390(M+H⁷⁹Br/⁸¹Br) (473.90446 cal.).

N-(Methanesulfonyl)-N-4-nitrobenzoyloxy-tert-butyl-carbamate (39). ¹HNMR (400 MHz, δ) 1.52 (9H, s), 3.49 (3H, s), 8.27 (2H, d), 8.31 (2H, d);¹³C NMR (100 MHz, δ) 27.85, 42.07, 87.40, 123.96, 131.22, 131.55,148.72, 151.43, 162.78; IR (KBr, cm⁻¹) 1762.2, 1795.0.

N-(2,6-Dichlorobenzenesulfonyl)-N-4-nitrobenzoyloxy)-tert-butyl-carbamate(40). ¹H NMR (400 MHz, δ) 1.39 (9H, s), 7.50-7.56 (3H, m), 8.33 (4H, m);¹³C NMR (100 MHz, δ) 27.76, 87.65, 123.93, 131.47, 131.64, 131.77,134.02, 134.11, 136.52, 147.86, 151.33, 162.00.

Example 4 Synthesis of Compounds 41-47, 50, 51, 53-78, 103-111 Synthesisof N,O Disubstituted Hydroxylamine Intermediates (Scheme 1)

To a stirred solution of N-hydroxy carbamate (1 equiv) in diethyl ether(50 vol) cooled to 0° C. is sequentially added triethylamine (1 equiv)and a solution of an acid chloride (1 equiv) in diethyl ether. Thereaction mixture is stirred at 0° C. until complete consumption of thestarting material is observed by tlc after which time the reaction isfiltered to remove triethylamine hydrochloride and the resultingfiltrate is washed with sodium bicarbonate solution (10 vol). Theresulting organics are dried over sodium sulfate, filtered andconcentrated in vacuo. The crude material is either used directlywithout additional purification or purified by column chromatographyeluting with heptane: ethyl acetate.

Synthesis of Compounds from N,O Disubstituted Hydroxylamine Intermediate(Scheme 2)

All compounds are synthesized via standard methods using the generalmethod detailed by H. T. Nagasawa et al., J. Med. Chem. 1992, 35,3648-3652. A solution of N,O-disubstituted hydroxylamine (1 equiv) inTHF (5 vol) is added dropwise to a stirred solution of sodium hydride(60% dispersion in oil, 1 equiv) in THF (5 vol). Stirring is continuedfor 30 minutes, whereupon a sulfonyl chloride (1 equiv) is added. Thereaction is stirred at room temperature until all starting material isconsumed (monitored by tlc). The reaction is quenched by the addition ofwater (10 vol) and extracted into ether (30 vol). The combined organicsare dried over sodium sulfate, filtered and concentrated in vacuo toyield the desired material, which is purified by silica columnchromatography eluting with heptane: ethyl acetate.

Preparation of tert-butyl (acetyloxy)[(2-bromophenyl)sulfonyl]carbamate(41)

[(tert-Butoxy)carbonyl]amino acetate is prepared from acetyl chlorideand N-tert-butoxycarbonyl hydroxylamine according to Scheme 1 and themethod described by Carpino et al. J. Am. Chem. Soc. 1959, 955-957. (10g, 100%), ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.57 (1H, br. s.), 2.10 (3H,s), 1.41 (9H, s).

tert-Butyl (acetyloxy)[(2-bromophenyl)sulfonyl]carbamate (41) isprepared according to Scheme 2. A solution of[(tert-butoxy)carbonyl]amino acetate (0.68 g, 3.9 mmol) in THF (5 ml) isadded dropwise to a stirred solution of sodium hydride (0.16 g of a 60%dispersion, 3.9 mmol) in THF (10 ml). Stirring is continued for 30minutes, whereupon 2-bromobenzene sulfonyl chloride (1.0 g, 3.9 mmol) isadded. The reaction mixture is stirred at room temperature for 3 hoursafter which time tlc (1:1 heptane:ethyl acetate) shows no startingmaterial remains. The reaction mixture is quenched by the addition ofwater (30 ml) and extracted into ether (2×50 ml). The combined organicsare dried over sodium sulfate, filtered and concentrated in vacuo toyield the desired material as a yellow oil, which is purified by silicacolumn chromatography eluting with heptane: ethyl acetate (4:1; v:v).(0.96 g, 60%), ¹H NMR (360 MHz, DMSO-d₆) δ ppm 8.12-8.26 (1H, m),7.87-8.06 (1H, m), 7.61-7.79 (2H, m), 2.32 (3H, s), 1.26 (9H, s).

Preparation of tert-butyl(acetyloxy){[2-(methylsulfonyl)phenyl]sulfonyl}carbamate (42)

tert-Butyl (acetyloxy){[2-(methylsulfonyl)phenyl]sulfonyl}carbamate (42)is prepared from 2-methylsulfonylbenzenesulfonyl chloride, sodiumhydride and [(tert-butoxy)carbonyl]amino acetate according to Scheme 2.(0.5 g, 16%), ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.26-8.34 (1H, m),8.17-8.25 (1H, m), 8.03-8.11 (2H, m), 3.46 (3H, s), 2.32 (3H, s), 1.28(9H, s).

Preparation of tert-butyl(acetyloxy)[(3-bromothiophen-2-yl)sulfonyl]carbamate (43)

tert-Butyl (acetyloxy)[(3-bromothiophen-2-yl)sulfonyl]carbamate (43) isprepared from 3-bromothiophene-2-sulfonyl chloride, sodium hydride and[(tert-butoxy)carbonyl]amino acetate according to Scheme 2. (0.8 g,35%), ¹H NMR (250 MHz, CHLOROFORM-d) δ ppm 7.68 (1H, d, 5.3 Hz), 7.15(1H, d, 5.2 Hz), 2.30 (3H, s), 1.48 (9H, s).

Preparation of tert-butyl{[2-(methylsulfonyl)phenyl]sulfonyl}(propanoyloxy)carbamate (44)

[(tert-Butoxy)carbonyl]amino propanoate is prepared from propionylchloride and N-tert-butoxycarbonyl hydroxylamine according to Scheme 1described by Carpino et al. J. Am. Chem. Soc. 1959, 955-957. (3.4 g,48%), ¹H NMR (250 MHz, DMSO-d₆) δ ppm 10.57 (1H, br. s.), 2.40 (2H, q,7.5 Hz), 1.40 (9H, s), 1.07 (3H, t, 7.4 Hz).

tert-Butyl {[2-(methylsulfonyl)phenyl]sulfonyl}(propanoyloxy)carbamate(44) is prepared from 2-methylsulfonylbenzenesulfonyl chloride, sodiumhydride and [(tert-butoxy)carbonyl]amino propanoate according to Scheme2. (1.09 g, 68%), ¹H NMR (250 MHz, DMSO-d₆) δ ppm 8.16-8.37 (2H, m),8.00-8.15 (2H, m), 3.46 (3H, s), 2.61 (2H, q, 7.5 Hz), 1.29 (9H, s),1.15 (3H, t, 7.5 Hz).

Preparation of tert-butyl[(2-methylpropanoyl)oxy]{[2-(methylsulfonyl)phenyl]sulfonyl}carbamate(45)

[(tert-Butoxy)carbonyl]amino 2-methylpropanoate is prepared fromisobutyryl chloride and N-tert-butoxycarbonyl hydroxylamine according toScheme 1 using the method described by Carpino et al. J. Am. Chem. Soc.1959, 955-957. (6.36 g, 83%), ¹H NMR (250 MHz, DMSO-d₆) δ ppm 10.51 (1H,br. s.), 2.65 (1H, sept, 7.0 Hz), 1.40 (9H, s), 1.13 (6H, d, 7.0 Hz).

tert-Butyl[(2-methylpropanoyl)oxy]{[2-(methylsulfonyl)phenyl]sulfonyl}carbamate(45) is prepared from 2-methylsulfonylbenzenesulfonyl chloride, sodiumhydride and [(tert-butoxy)carbonyl]amino 2-methylpropanoate according toScheme 2. (1.2 g, 72%), ¹H NMR (250 MHz, DMSO-d₆) δ ppm 8.18-8.34 (2H,m), 8.00-8.14 (2H, m), 3.46 (3H, s), 2.86 (1H, sept, 7.1 Hz), 1.29 (9H,s), 1.21 (6H, d, 7.0 Hz).

Preparation of tert-butyl[(2,2-dimethylpropanoyl)oxy]{[2-(methylsulfonyl)phenyl]sulfonyl}carbamate(46)

[(tert-Butoxy)carbonyl]amino 2,2-dimethylpropanoate is prepared fromtrimethyl acetyl chloride and N-tert-butoxycarbonyl hydroxylamineaccording to Scheme 1 described by Carpino et al. J. Am. Chem. Soc.1959, 955-957. (6.4 g, 78%), ¹H NMR (250 MHz, DMSO-d₆) δ ppm 10.46 (1H,br. s.), 1.40 (9H, s), 1.20 (9H, s).

tert-Butyl[(2,2-dimethylpropanoyl)oxy]{[2-(methylsulfonyl)phenyl]sulfonyl}carbamate(46) is prepared from 2-methylsulfonylbenzenesulfonyl chloride, sodiumhydride and [(tert-butoxy)carbonyl]amino 2,2-dimethylpropanoateaccording to Scheme 2. (1.5 g, 78%), ¹H NMR (250 MHz, DMSO-d₆) δ ppm8.18-8.37 (2H, m), 7.94-8.15 (2H, m), 3.46 (3H, s), 1.30 (9H, s), 1.29(9H, s).

Preparation of tert-butyl {[2-(methylsulfonyl)phenyl]sulfonyl}[(phenylcarbonyl)oxy]carbamate (47)

[(tert-Butoxy)carbonyl]amino benzoate is prepared from benzoyl chlorideand N-tert-butoxycarbonyl hydroxylamine according to Scheme 1 describedby Carpino et al. J. Am. Chem. Soc. 1959, 955-957. (7.2 g, 80%), ¹H NMR(250 MHz, DMSO-d₆) δ ppm 10.89 (1H, br. s.), 7.90-8.12 (2H, m),7.68-7.82 (1H, m), 7.51-7.65 (2H, m), 1.43 (9H, s).

tert-Butyl{[2-(methylsulfonyl)phenyl]sulfonyl}[(phenylcarbonyl)oxy]carbamate (47)is prepared from 2-methylsulfonylbenzenesulfonyl chloride, sodiumhydride and [(tert-butoxy)carbonyl]amino benzoate according to Scheme 2.(1.7 g, 91%), ¹H NMR (250 MHz, DMSO-d₆) δ ppm 8.25-8.45 (2H, m),8.03-8.20 (4H, m), 7.77-7.93 (1H, m), 7.59-7.73 (2H, m), 3.48 (3H, s),1.29 (9H, s).

Preparation of benzyl(acetyloxy){[2-(methylsulfonyl)phenyl]sulfonyl}carbamate (50)

[(Benzyloxy)carbonyl]amino acetate is prepared fromN-(benzyloxycarbonyl) hydroxylamine and acetyl chloride according toScheme 1. (1.24 g, 33%), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.18 (1H,br. s.), 7.32-7.45 (5H, m), 5.22 (2H, s), 2.22 (3H, s).

Benzyl (acetyloxy){[2-(methylsulfonyl)phenyl]sulfonyl}carbamate (50) isprepared from 2-methylsulfonylbenzenesulfonyl chloride, sodium hydrideand [(benzyloxy) carbonyl]amino acetate according to Scheme 2. (0.33 g,28%), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.21-8.47 (2H, m), 7.79-7.88(1H, m), 7.65-7.74 (1H, m), 7.30-7.41 (3H, m), 7.16-7.24 (2H, m), 5.18(2H, br. s.), 3.31 (3H, s), 2.29 (3H, s).

Preparation of benzyl{[2-(methylsulfonyl)phenyl]sulfonyl}(propanoyloxy)carbamate (51)

[(Benzyloxy)carbonyl]amino propanoate is prepared fromN-(benzyloxycarbonyl) hydroxylamine and propionyl chloride according toScheme 1. (3.6 g, 89%), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.18 (1H,s), 7.32-7.43 (5H, m), 5.22 (2H, s), 2.50 (2H, q, 7.6 Hz), 1.22 (3H, t,7.6 Hz).

Benzyl {[2-(methylsulfonyl)phenyl]sulfonyl}(propanoyloxy)carbamate (51)is prepared from 2-methylsulfonylbenzenesulfonyl chloride, sodiumhydride and [(benzyloxy)carbonyl]-amino propanoate according to Scheme2. (0.56 g, 50%), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.39 (1H, d, 7.9Hz), 8.35 (1H, d, 7.9 Hz), 7.80-7.86 (1H, m), 7.68-7.73 (1H, m),7.30-7.39 (3H, m), 7.18-7.23 (2H, m), 5.17 (2H, br. s.), 3.30 (3H, s),2.58 (2H, br. s.), 1.23 (3H, t, 7.5 Hz).

Preparation ofN-[(tert-butoxy)carbonyl][2-chloro-5-(dimethylcarbamoyl)benzene]sulfonamido2,2-dimethylpropanoate (53) 4-Chloro-3-(chlorosulfonyl)benzoic acid

The following method for the chorosulfonylation of benzoic acids isdescribed in Bioorg. Med. Chem. 2002, 639-656:

To a flask containing chlorosulfonic acid (17 ml, 250 mmol) cooled to 0°C. is added 4-chlorobenzoic acid (5.2 g, 33.3 mmol) portionwise. Thereaction mixture is heated to 130° C. for 24 hours or until completeconsumption of the starting material. The reaction mixture is cooled toambient temperature before careful addition to ice. The resulting solidis filtered and washed with cold water (50 ml). The wet product isdissolved in diethyl ether (100 ml), dried over sodium sulfate, filteredand concentrated in vacuo to yield the title compound without need foradditional purification. (6.1 g, 71%), ¹H NMR (500 MHz, MeOD) δ ppm 8.57(1H, s), 7.42-7.76 (2H, m).

4-Chloro-3-(chlorosulfonyl)benzoyl chloride

4-Chloro-3-(chlorosulfonyl)benzoic acid (6.1 g, 24 mmol) is suspended intoluene (50 ml). Thionyl chloride (3.5 ml, 47 mmol) is added dropwise,and the mixture is heated to reflux for 14 hours under nitrogen untilcomplete consumption of the carboxylic acid is observed by LCMS. Thereaction mixture is concentrated to dryness to afford the expected acidchloride which is used for next step without further purification.

2-Chloro-5-(dimethylcarbamoyl)benzene-1-sulfonyl chloride

The following method is described in Journal of Pharmacy andPharmacology 1963, 202-211:

Dimethylamine hydrochloride (0.5 g, 6.2 mmol) is added to a stirredsolution of 4-chloro-3-(chlorosulfonyl)benzoyl chloride (1.6 g, 5.88mmol) in chlorobenzene (10 ml). The reaction mixture is heated to refluxfor 2 hours, or until complete consumption of the starting material isobserved by LCMS. The reaction mixture is concentrated to dryness andthe residue is taken up in diethyl ether (20 ml). The precipitate isfiltered and washed with diethyl ether (2×10 ml) to afford the titlecompound. (1.1 g, 64%), ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.86 (1H, d, 2.0Hz), 7.43 (1H, d, 8.1 Hz), 7.34 (1H, dd, 8.1, 2.2 Hz), 2.97 (3H, br. s),2.90 (3H, br. s).

N-[(tert-Butoxy)carbonyl][2-chloro-5-(dimethylcarbamoyl)benzene]sulfonamido2,2-dimethylpropanoate (53) is synthesised from2-chloro-5-(dimethylcarbamoyl)benzene-1-sulfonyl chloride, sodiumhydride and [(tert-butoxy)carbonyl]amino 2,2-dimethylpropanoateaccording to Scheme 2. (0.5 g, 40%), ¹H NMR (250 MHz, DMSO-d₆) δ ppm8.04 (1H, s), 7.46-7.79 (2H, m), 2.92 (3H, br. s.), 2.83 (3H, br. s.),1.18 (9H, s) 1.12 (9H, s).

Preparation of N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido 2-(acetyloxy)benzoate (54)

[(tert-Butoxy)carbonyl]amino 2-(acetyloxy)benzoate is prepared fromacetylsalicyloyl chloride and N-tert-butoxycarbonyl hydroxylamineaccording to Scheme 1 described by Carpino et al. J. Am. Chem. Soc.1959, 955-957. ¹H NMR (250 MHz, DMSO-d₆) δ ppm 10.89 (1H, br. s.), 7.97(1H, dd, 7.8, 1.7 Hz), 7.75 (1H, td, 7.8, 1.8 Hz), 7.46 (1H, td, 7.6,1.1 Hz), 7.31 (1H, dd, 8.1, 0.9 Hz), 2.27 (3H, s), 1.42 (9H, s).

N-[(tert-Butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido2-(acetyloxy)benzoate (54) is synthesised from2-methylsulfonylbenzenesulfonyl chloride, sodium hydride and[(tert-butoxy)carbonyl]amino 2-(acetyloxy)benzoate according to Scheme2. (5.5 g, 89%), ¹H NMR (250 MHz, DMSO-d₆) δ ppm 8.34-8.43 (1H, m),8.07-8.21 (3H, m), 7.94-8.05 (1H, m), 7.77 (1H, td, 7.9, 1.8 Hz),7.56-7.66 (1H, m), 7.07-7.16 (1H, m), 3.45 (3H, s), 2.48 (3H, s.), 1.43(9H, s).

Preparation of N-[(tert-butoxy)carbonyl]-1-benzofuran-2-sulfonamido2,2-dimethylpropanoate (55)

N-[(tert-Butoxy)carbonyl]1-benzofuran-2-sulfonamido2,2-dimethylpropanoate (55) is prepared from[(tert-butoxy)carbonyl]amino 2,2-dimethylpropanoate, sodium hydride and1-benzofuran-2-sulfonyl chloride according to Scheme 2. (4.0 g, 87%), ¹HNMR (250 MHz, DMSO-d₆) δ ppm 8.06 (1H, d, 0.8 Hz), 7.92 (1H, d, 7.3 Hz),7.81 (1H, dd, 8.5, 0.8 Hz), 7.64 (1H, ddd, 8.5, 7.2, 1.4 Hz), 7.42-7.53(1H, m), 1.37 (9H, s), 1.28 (9H, s).

Preparation of N-[(tert-butoxy)carbonyl]-1-benzofuran-2-sulfonamidoacetate (56)

N-[(tert-Butoxy)carbonyl]-1-benzofuran-2-sulfonamido acetate (56) isprepared from [(tert-butoxy)carbonyl]amino acetate, sodium hydride and1-benzofuran-2-sulfonyl chloride according to Scheme 2. (3.1 g, 75%), ¹HNMR (250 MHz, DMF) δ ppm 8.07 (1H, d, 0.9 Hz), 7.91 (1H, d, 7.3 Hz),7.82 (1H, dd, 8.5, 0.8 Hz), 7.64 (1H, td, 7.8, 1.4 Hz), 7.41-7.52 (1H,m), 2.32 (3H, s), 1.37 (9H, s).

Preparation of N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamidobenzoate (57)

N-[(tert-Butoxy)carbonyl](2-bromobenzene)sulfonamido benzoate (57) issynthesised from 2-bromobenzenesulfonyl chloride, sodium hydride and[(tert-butoxy)carbonyl]amino benzoate according to Scheme 2. (4.8 g,87%), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.34 (1H, dd, 7.6, 2.1 Hz),8.12-8.22 (2H, m), 7.82 (1H, dd, 7.5, 1.7 Hz), 7.63-7.70 (1H, m),7.48-7.57 (4H, m), 1.39 (9H, s).

Preparation of N-[(tert-butoxy)carbonyl]3-bromothiophene-2-sulfonamido2,2-dimethylpropanoate (58)

N-[(tert-Butoxy)carbonyl]3-bromothiophene-2-sulfonamido2,2-dimethylpropanoate (58) is synthesised from3-bromothiophene-2-sulfonyl chloride (synthesised according to themethod detailed in Bioorganic and Medicinal Chemistry Letters 1996, 6,2651-2656), sodium hydride and [(tert-Butoxy)carbonyl]amino2,2-dimethylpropanoate according to Scheme 2. (0.2 g, 12%), ¹H NMR (500MHz, DMSO-d₆) δ ppm 8.25 (1H, d, 5.2 Hz), 7.44 (1H, d, 5.2 Hz), 1.39(9H, s), 1.29 (9H, s).

Preparation of N-[(tert-butoxy)carbonyl]3-chlorothiophene-2-sulfonamido2,2-dimethylpropanoate (59)

3-Chlorothiophene-2-sulfonyl chloride is synthesised according to themethod detailed in Bioorganic and Medicinal Chemistry Letters 1996, 6,2651-2656:

To a stirred solution of 3-chlorothiophene (10 g, 84 mmol) indichloromethane (25 ml) cooled to 0° C. is added chlorosulfonic acid (16ml, 252 mmol) dropwise. The reaction mixture is then stirred for 2 hoursat 0° C. is and then carefully poured onto ice and extracted intodichloromethane (2×250 ml). The organics are combined and dried oversodium sulfate, filtered and concentrated in vacuo to afford the titlecompound as a mixture with the other isomer. Both isomers are separatedand the title compound isolated by silica column chromatography elutingwith hexane:ethyl acetate. (3.7 g, 20%), ¹H NMR (500 MHz, CHLOROFORM-d)δ ppm 7.75 (1H, d, 5.3 Hz), 7.15 (1H, d, 5.3 Hz).

N-[(tert-Butoxy)carbonyl]3-chlorothiophene-2-sulfonamido2,2-dimethylpropanoate (59) is synthesised from3-chlorothiophene-2-sulfonyl chloride, sodium hydride and[(tert-butoxy)carbonyl]amino 2,2-dimethylpropanoate according to Scheme2. (1.72 g, 94%), ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.29 (1H, d, 5.3 Hz),7.40 (1H, d, 5.2 Hz), 1.39 (9H, s), 1.28 (9H, s).

Preparation of N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamido2-methylpropanoate (60)

N-[(tert-Butoxy)carbonyl](2-bromobenzene)sulfonamido 2-methylpropanoate(60) is prepared from 2-bromobenzene sulfonyl chloride, sodium hydrideand [(tert-butoxy)carbonyl]amino 2-methylpropanoate according to Scheme2. (1.96 g, 59%), ¹H NMR (250 MHz, CHLOROFORM-d) δ ppm 8.23-8.37 (1H,m), 7.72-7.88 (1H, m), 7.42-7.59 (2H, m), 2.67-3.02 (1H, m), 1.37 (9H,s), 1.34 (3H, s), 1.32 (3H, s).

Preparation of N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamido2,2-dimethylpropanoate (61)

N-[(tert-Butoxy)carbonyl](2-bromobenzene)sulfonamido2,2-dimethylpropanoate (61) is prepared from 2-bromobenzene sulfonylchloride, sodium hydride and [(tert-butoxy)carbonyl]amino2,2-dimethylpropanoate according to Scheme 2. (2.57 g, 75%), ¹H NMR (250MHz, CHLOROFORM-d) δ ppm 8.13-8.52 (1H, m), 7.71-7.96 (1H, m), 7.38-7.61(2H, m), 2.64-3.03 (1H, m), 1.37 (9H, s), 1.33 (6H, d, 7.0 Hz).

Preparation of N-[(tert-butoxy)carbonyl](2-chlorobenzene)sulfonamido2,2-dimethylpropanoate (62)

N-[(tert-Butoxy)carbonyl](2-chlorobenzene)sulfonamido2,2-dimethylpropanoate (62) is prepared from 2-chlorobenzenesulfonylchloride, sodium hydride and [(tert-butoxy)carbonyl]-amino2,2-dimethylpropanoate according to Scheme 2. (4.1 g, 81%), ¹H NMR (250MHz, CHLOROFORM-d) δ ppm 7.63-7.70 (1H, m), 7.55-7.6 (2H, m), 7.40-7.50(1H, m), 1.38 (9H, s), 1.37 (9H, s).

Preparation of N-[(tert-butoxy)carbonyl][2-chloro-5-(dimethylcarbamoyl)benzene]sulfonamido-acetate (63)

N-[(tert-Butoxy)carbonyl][2-chloro-5(dimethylcarbamoyl)benzene]sulfonamidoacetate (63) is prepared from2-chloro-5-(dimethylcarbamoyl)benzene-1-sulfonyl chloride, sodiumhydride and [(tert-butoxy)carbonyl]amino acetate according to Scheme 2.(1.2 g, 95%), ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.11 (1H, s), 7.87 (2H,s), 3.00 (3H, s), 2.91 (3H, s), 1.40 (3H, s), 1.29 (9H, s).

Preparation of N-[(tert-butoxy)carbonyl](2-chlorobenzene)sulfonamido2-methylpropanoate (64)

N-[(tert-Butoxy)carbonyl](2-chlorobenzene)sulfonamido 2-methylpropanoate(64) is prepared from 2-chlorobenzene sulfonyl chloride, sodium hydrideand [(tert-butoxy)carbonyl]amino 2-methylpropanoate according to Scheme2. (3.4 g, 91%), ¹H NMR (250 MHz, CHLOROFORM-d) δ ppm 8.16-8.29 (1H, m),7.52-7.63 (2H, m), 7.39-7.51 (1H, m), 2.86 (1H, quin, 7.0 Hz), 1.38 (9H,s), 1.33 (6H, d, 7.0 Hz).

Preparation of N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamido2-phenylacetate (65)

[(tert-Butoxy)carbonyl]amino 2-phenylacetate is prepared fromphenylacetyl chloride and N-tert-butoxycarbonyl hydroxylamine accordingto Scheme 1 using literature conditions. (8.8 g, 100%), ¹H NMR (500 MHz,DMSO-d₆) δ ppm 10.66 (1H, br. s.), 7.24-7.38 (5H, m), 3.80 (2H, s), 1.38(9H, s).

N-[(tert-Butoxy)carbonyl](2-bromobenzene)sulfonamido 2-phenylacetate(65) is prepared from 2-bromobenzene sulfonyl chloride, sodium hydrideand [(tert-butoxy)carbonyl]amino 2-phenylacetate according to Scheme 2.¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.16-8.23 (1H, m), 7.95-8.00 (1H, m),7.66-7.75 (2H, m), 7.26-7.41 (5H, m), 4.04 (2H, s), 1.24 (9H, s).

Preparation of N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamido2-methyl-2-phenylpropanoate (66) [(tert-butoxy)carbonyl]amino2-methyl-2-phenylpropanoate

A solution of α,α dimethyl phenylacetic acid (2 g, 12.18 mmol) inthionyl chloride (20 ml) is heated to reflux for 1 hour after which timeall of the starting acid has been consumed. The reaction mixture isconcentrated in vacuo and the resulting acid chloride is used directlyfor the synthesis of [(tert-butoxy)carbonyl]amino2-methyl-2-phenylpropanoate, which is prepared from the described acidchloride and N-tert-butoxycarbonyl hydroxylamine according to Scheme 1.(2.76 g, 81%), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.64 (1H, s), 7.29(4H, dt, 15.6, 7.8 Hz), 7.12-7.23 (1H, m), 1.60 (6H, s), 1.38 (9H, s).

N-[(tert-Butoxy)carbonyl](2-bromobenzene)sulfonamido 2-methyl-2-phenylpropanoate (66) is prepared from 2-bromobenzene sulfonyl chloride,sodium hydride and [(tert-butoxy)carbonyl]amino2-methyl-2-phenylpropanoate according to Scheme 2. (1.46 g, 82%), ¹H NMR(500 MHz, CHLOROFORM-d) δ ppm 8.12-8.21 (1H, m), 7.65-7.78 (1H, m),7.41-7.49 (4H, m), 7.37 (2H, t, 7.7 Hz), 7.26-7.31 (1H, m), 1.75 (6H,s), 1.36 (9H, s).

Preparation of N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamido1-phenylcyclopentane-1-carboxylate (67) [(tert-Butoxy)carbonyl]amino1-phenylcyclopentane-1-carboxylate

A solution of 1-phenyl cyclopentane carboxylic acid (2 g, 10.5 mmol) inthionyl chloride (20 ml) is heated to reflux for 1 hour after which timeall of the starting acid has been consumed. The reaction mixture isconcentrated in vacuo and the resulting acid chloride used directly forthe synthesis [(tert-butoxy)carbonyl]amino1-phenylcyclopentane-1-carboxylate, which is prepared from the describedacid chloride and N-tert-butoxycarbonyl hydroxylamine according toScheme 1. (2.4 g, 75%), ¹H NMR (250 MHz, CHLOROFORM-d) δ ppm 7.62 (1H,s), 7.18-7.49 (5H, m), 2.63-2.86 (2H, m), 1.93-2.11 (2H, m), 1.71-1.90(4H, m), 1.45 (9H, s).

N-[(tert-Butoxy)carbonyl](2-bromobenzene)sulfonamido1-phenylcyclopentane-1-carboxylate (67) is synthesised from2-bromobenzene sulfonyl chloride, sodium hydride and[(tert-butoxy)carbonyl]amino 1-phenylcyclopentane-1-carboxylateaccording to Scheme 2. (1.41 g, 82%), ¹H NMR (500 MHz, CHLOROFORM-d) δppm 8.09-8.18 (1H, m), 7.62-7.75 (1H, m), 7.38-7.49 (4H, m), 7.34 (2H,t, 7.6 Hz), 7.23-7.30 (1H, m), 2.68-2.94 (2H, m), 1.76-2.17 (6H, m),1.29 (9H, s).

Preparation of 2-N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamido-1-tert-butyl pyrrolidine-1,2-dicarboxylate (68)

2-[(tert-Butoxy)carbonyl]amino-1-tert-butylpyrrolidine-1,2-dicarboxylate is synthesised using the method detailedin Tetrahedron 1994, 5049-5066. (1.78 g, 81%), ¹H NMR (250 MHz,CHLOROFORM-d) δ ppm 7.56-8.33 (1H, s), 4.43 (1H, ddd, 15.6, 8.3, 4.3Hz), 3.20-3.85 (2H, m), 2.11-2.39 (2H, m), 1.81-2.10 (2H, m), 1.56-1.65(9H, s), 1.49 (9H, s).

2-N-[(tert-Butoxy)carbonyl](2-bromobenzene)sulfonamido-1-tert-butylpyrrolidine-1,2-dicarboxylate (68) is synthesised from 2-bromobenzenesulfonyl chloride, sodium hydride and 2-[(tert-butoxy)carbonyl]amino1-tert-butyl pyrrolidine-1,2-dicarboxylate according to Scheme 2. (0.97g, 73%), ¹H NMR (250 MHz, CHLOROFORM-d) δ ppm 8.21-8.32 (1H, m),7.72-7.84 (1H, m), 7.41-7.58 (2H, m), 4.55-4.70 (1H, m), 3.53-3.68 (1H,m), 3.31-3.53 (1H, m), 2.22-2.42 (2H, m), 1.85-2.14 (2H, m), 1.44-1.50(9H, s), 1.38 (9H, s).

Preparation of N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamido2-[4-(dimethylamino)phenyl]acetate (69) [(tert-Butoxy)carbonyl]amino2-[4-(dimethylamino)phenyl]acetate

To a solution of 4-dimethylamino phenyl acetic acid (2.0 g, 11.6 mmol)in DCM (20 ml) is added EDCI.HCl (3.2 g, 16.74 mmol) and triethylamine(4.7 ml, 33.48 mmol). The reaction is stirred for 30 minutes beforeaddition of N-tert-butoxycarbonyl hydroxylamine (2.2 g, 16.74 mmol). Thereaction is stirred for 18 hours then quenched with water (10 ml). Theorganics are separated, washed twice with water (2×5 ml), dried oversodium sulfate and concentrated in vacuo. Purification of the titlecompound is achieved by silica gel column chromatography eluting withheptane: ethyl acetate (4:1, v:v). (2.08 g, 63%), ¹H NMR (250 MHz,CHLOROFORM-d) δ ppm 7.89 (1H, s), 7.11-7.23 (2H, m), 6.63-6.76 (2H, m),2.94 (6H, s), 1.47 (9H, s).

N-[(tert-Butoxy)carbonyl](2-bromobenzene)sulfonamido2-[4-(dimethylamino)phenyl]acetate (69) is synthesised from2-bromobenzene sulfonyl chloride, sodium hydride and[(tert-butoxy)carbonyl]amino 2-[4-(dimethylamino)phenyl]acetateaccording to Scheme 2. (0.39 g, 23%), ¹H NMR (500 MHz, CHLOROFORM-d) δppm 8.16-8.33 (1H, m), 7.74-7.82 (1H, m), 7.43-7.54 (2H, m), 7.21 (2H,d, 8.5 Hz), 6.71 (2H, d, 8.1 Hz), 3.80 (2H, s), 2.94 (6H, s), 1.34 (9H,s).

Preparation of N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamido1-acetylpyrrolidine-2-carboxylate (70)

[(tert-Butoxy)carbonyl]amino-1-acetyl-L-pyrrolidine-2-carboxylate issynthesised using the method detailed in Tetrahedron 1994, 5049-5066.(1.05 g, 36%), ¹H NMR (250 MHz, CHLOROFORM-d) δ ppm 8.15 (1H, br. s.),4.49-4.73 (1H, m), 3.60-3.74 (1H, m), 3.45-3.59 (1H, m), 2.13-2.41 (2H,m), 2.10 (3H, s), 1.91-2.08 (2H, m), 1.41-1.51 (9H, m).

N-[(tert-Butoxy)carbonyl](2-bromobenzene)sulfonamido1-acetyl-L-pyrrolidine-2-carboxylate (70) is synthesised from2-bromobenzene sulfonyl chloride, sodium hydride and[(tert-butoxy)carbonyl]amino-1-acetyl-L-pyrrolidine-2-carboxylateaccording to Scheme 2. (0.66 g, 35%), ¹H NMR (500 MHz, CHLOROFORM-d) δppm 8.21-8.34 (1H, m), 7.75-7.83 (1H, m), 7.44-7.56 (2H, m), 4.51-4.65(1H, m), 3.63-3.77 (1H, m), 3.45-3.62 (1H, m), 2.31-2.55 (2H, m),2.15-2.31 (2H, m), 2.11 (3H, s), 1.49 (9H, s).

Preparation of N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamido(2S)-2-phenylpropanoate (71)

[(tert-Butoxy)carbonyl]amino (2S)-2-phenylpropanoate is synthesisedusing the method detailed in Tetrahedron 1994, 5049-5066. (2.57 g, 73%),¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.77 (1H, s), 7.33-7.37 (4H, m),7.28-7.32 (1H, m), 3.90 (1H, q, 7.2 Hz), 1.60 (3H, d, 7.3 Hz), 1.45 (9H,s).

N-[(tert-Butoxy)carbonyl](2-bromobenzene)sulfonamido(2S)-2-phenylpropanoate (71) is synthesised from 2-bromobenzene sulfonylchloride, sodium hydride and [(tert-butoxy)carbonyl]amino(2S)-2-phenylpropanoate according to Scheme 2. (0.36 g, 20%), ¹H NMR(500 MHz, CHLOROFORM-d) δ ppm 8.10 (1H, d, 8.2 Hz), 7.81-7.91 (1H, m),7.79 (1H, d, 8.2 Hz), 7.33-7.41 (5H, m), 6.95-7.05 (1H, m), 4.13 (1H, q,7.1 Hz), 1.67 (3H, d, 7.2 Hz), 1.59 (9H, s).

Preparation of N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamido(2R)-2-phenylpropanoate (72)

[(tert-Butoxy)carbonyl]amino (2R)-2-phenylpropanoate is synthesisedusing the method detailed in Tetrahedron 1994, 5049-5066. (0.92 g, 69%),¹H NMR (250 MHz, CHLOROFORM-d) δ ppm 7.78 (1H, s), 7.15-7.40 (5H, m),3.90 (1H, q, 7.1 Hz), 1.60 (3H, d, 7.2 Hz), 1.45 (9H, s).

N-[(tert-Butoxy)carbonyl](2-bromobenzene)sulfonamido(2R)-2-phenylpropanoate (72) is synthesised from 2-bromobenzene sulfonylchloride, sodium hydride and [(tert-butoxy)carbonyl]amino(2R)-2-phenylpropanoate according to Scheme 2. (0.66 g, 35%), ¹H NMR(500 MHz, CHLOROFORM-d) δ ppm 8.02-8.36 (1H, m), 7.67-7.85 (1H, m),7.28-7.53 (7H, m), 3.89-4.06 (1H, m), 1.66 (3H, d, 7.2 Hz), 1.37 (9H,s).

Preparation of N-[(tert-butoxy)carbonyl]-5-chlorothiophene-2-sulfonamido2-methylpropanoate (73)

N-[(tert-Butoxy)carbonyl]-5-chlorothiophene-2-sulfonamido2-methylpropanoate (73) is synthesised from 5-chlorothiophene sulfonylchloride, sodium hydride and [(tert-butoxy)carbonyl]amino2-methylpropanoate according to Scheme 2. (1.7 g, 100%), ¹H NMR (500MHz, CHLOROFORM-d) δ ppm 7.65 (1H, d, 4.1 Hz), 6.99 (1H, d, 4.1 Hz),2.81 (1H, sept, 7.0 Hz), 1.49 (9H, s), 1.31 (6H, d, 7.0 Hz).

Preparation of N-[(tert-butoxy)carbonyl]-5-chlorothiophene-2-sulfonamido2,2-dimethylpropanoate (74)

N-[(tert-Butoxy)carbonyl]-5-chlorothiophene-2-sulfonamido2,2-dimethylpropanoate (74) is synthesised from 5-chlorothiophenesulfonyl chloride, sodium hydride and [(tert-butoxy)carbonyl]amino2,2-dimethylpropanoate according to Scheme 2. (1.89 g, 100%), ¹H NMR(500 MHz, CHLOROFORM-d) δ ppm 7.65 (1H, d, 4.1 Hz), 6.99 (1H, d, 4.1Hz), 1.48 (9H, s), 1.35 (9H, s).

Preparation of N-[(tert-butoxy)carbonyl](3-methanesulfonylbenzene)sulfonamido 2,2-dimethylpropanoate (75)

N-[(tert-Butoxy)carbonyl](3-methanesulfonylbenzene) sulfonamido2,2-dimethylpropanoate (75) is synthesised from 2-methanesulfonylbenzenesulfonyl chloride, sodium hydride and [(tert-butoxy)carbonyl]amino2,2-dimethylpropanoate according to Scheme 2. (0.63 g, 37%), ¹H NMR (500MHz, CHLOROFORM-d) δ ppm 8.60 (1H, s), 8.35 (1H, d, 7.9 Hz), 8.26 (1H,d, 7.8 Hz), 7.81 (1H, t, 7.9 Hz), 1.43 (9H, s), 1.37 (9H, s).

Preparation of N-[(tert-butoxy)carbonyl](3-methanesulfonylbenzene)sulfonamido 2-methylpropanoate (76)

N-[(tert-Butoxy)carbonyl](3-methanesulfonylbenzene) sulfonamido 2-methylpropanoate (76) is synthesised from 2-methanesulfonylbenzene sulfonylchloride, sodium hydride and [(tert-butoxy)carbonyl]amino2-methylpropanoate according to Scheme 2. (1.3 g, 78%), ¹H NMR (500 MHz,CHLOROFORM-d) δ ppm 8.60 (1H, t, 1.7 Hz), 8.35 (1H, d, 7.9 Hz), 8.26(1H, d, 7.8 Hz), 7.82 (1H, t, 7.9 Hz), 2.78-2.88 (1H, m), 1.43 (9H, s),1.33 (6H, d, 7.0 Hz).

Preparation of N-[(tert-butoxy)carbonyl]pyridine-3-sulfonamido2,2-dimethylpropanoate (77)

N-[(tert-Butoxy)carbonyl]pyridine-3-sulfonamido 2,2-dimethylpropanoate(77) is synthesised from 3-pyridine sulfonyl chloride, sodium hydrideand [(tert-butoxy)carbonyl]amino 2,2-dimethylpropanoate according toScheme 2. (0.99 g, 58%), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.16-9.26(1H, m), 8.89 (1H, d, 4.4 Hz), 8.36 (1H, d, 8.2 Hz), 7.54 (1H, dd, 8.2,4.9 Hz), 1.42 (9H, s), 1.37 (9H, s)

Preparation of N-[(tert-butoxy)carbonyl]pyridine-3-sulfonamido2-methylpropanoate (78)

N-[(tert-Butoxy)carbonyl]pyridine-3-sulfonamido 2-methylpropanoate (78)is synthesised from 3-pyridine sulfonyl chloride, sodium hydride and[(tert-butoxy)carbonyl]amino 2-methylpropanoate according to Scheme 2.(0.6 g, 37%), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.21 (1H, d, 1.6 Hz),8.89 (1H, dd, 4.7, 1.3 Hz), 8.34 (1H, dd, 7.4, 1.4 Hz), 7.53 (1H, dd,8.2, 4.9 Hz), 2.84 (1H, sept, 7.0 Hz), 1.42 (9H, s), 1.32 (6H, d, 6.9Hz).

Tert-butyl(acetyloxy)[(3-bromothiophen-2-yl)sulfonyl]carbamate (103) isprepared from 3-bromothiphene-2-sulfonyl chloride, sodium hydride and[(tert-butoxy)carbonyl]aminoacetate according to Scheme 2. δH (250 MHz,CHLOROFORM-d) 7.68 (1H, d, 5.3 Hz), 7.15 (1H, d, 5.2 Hz), 2.30 (3H, s),1.48 (9H, s).

N-[(tert-Butoxy)carbonyl]1-benzofuran-2-sulfonamido2,2-dimethylpropanoate (104) is prepared from[(tert-butoxy)carbonyl]amino 2,2-dimethylpropanoate, sodium hydride and1-benzofuran-2-sulfonyl chloride according to Scheme 2. δH (250 MHz,DMSO-d₆) 8.06 (1H, d, 0.8 Hz), 7.92 (1H, d, 7.3 Hz), 7.81 (1H, dd, 8.5,0.8 Hz), 7.64 (1H, ddd, 8.5, 7.2, 1.4 Hz), 7.42-7.53 (1H, m), 1.37 (9H,s), 1.28 (9H, s).

N-[(tert-Butoxy)carbonyl]1-benzofuran-2-sulfonamido acetate (105) isprepared from [(tert-butoxy)carbonyl]amino acetate, sodium hydride and1-benzofuran-2-sulfonyl chloride according to Scheme 2. δH (250 MHz,DMF) 8.07 (1H, d, 0.9 Hz), 7.91 (1H, d, 7.3 Hz), 7.82 (1H, dd, 8.5, 0.8Hz), 7.64 (1H, td, 7.8, 1.4 Hz), 7.41-7.52 (1H, m), 2.32 (3H, s), 1.37(9H, s).

N-[(tert-Butoxy)carbonyl]3-bromothiophene-2-sulfonamido2,2-dimethylpropanoate (106) is synthesised from3-bromothiophene-2-sulfonyl chloride (synthesised according to themethod detailed in Bioorganic and Medicinal Chemistry Letters 1996, 6,2651-2656), sodium hydride and [(tert-Butoxy)carbonyl]amino2,2-dimethylpropanoate according to Scheme 2. δH (500 MHz, DMSO-d₆) 8.25(1H, d, 5.2 Hz), 7.44 (1H, d, 5.2 Hz), 1.39 (9H, s), 1.29 (9H, s).

N-[(tert-Butoxy)carbonyl]3-chlorothiophene-2-sulfonamido2,2-dimethylpropanoate (107) is synthesised from3-chlorothiophene-2-sulfonyl chloride, sodium hydride and[(tert-butoxy)carbonyl]amino 2,2-dimethylpropanoate according to Scheme2. δH (500 MHz, DMSO-d₆) 8.29 (1H, d, 5.3 Hz), 7.40 (1H, d, 5.2 Hz),1.39 (9H, s), 1.28 (9H, s).

3-Chlorothiophene-2-sulfonyl chloride is synthesised according to themethod detailed in Bioorganic and Medicinal Chemistry Letters 1996, 6,2651-2656. To a stirred solution of 3-chlorothiophene (10 g, 84 mmol) indichloromethane (25 ml) cooled to 0° C. is added chlorosulfonic acid (16ml, 252 mmol) dropwise. After 2 hours at 0° C., the reaction mixture iscarefully poured onto ice and extracted into dichloromethane (2×250 ml).The organics are combined and dried over sodium sulfate, filtered andconcentrated in vacuo to afford the title compound as a mixture with theother isomer. Both isomers are separated and the title compound isolatedby silica column chromatography eluting with hexane:ethyl acetate (3.7g, 20%). δH (500 MHz, CHLOROFORM-d) 7.75 (1H, d, 5.3 Hz), 7.15 (1H, d,5.3 Hz).

N-[(tert-Butoxy)carbonyl]5-chlorothiophene-2-sulfonamido2-methylpropanoate (108) is synthesised from 5-chlorothiophene sulfonylchloride, sodium hydride and [(tert-butoxy)carbonyl]amino2-methylpropanoate according to Scheme 2. δH (500 MHz, CHLOROFORM-d)7.65 (1H, d, 4.1 Hz), 6.99 (1H, d, 4.1 Hz), 2.81 (1H, sept, 7.0 Hz),1.49 (9H, s), 1.31 (6H, d, 7.0 Hz).

N-[(tert-Butoxy)carbonyl]5-chlorothiophene-2-sulfonamido2,2-dimethylpropanoate (109) is synthesised from 5-chlorothiophenesulfonyl chloride, sodium hydride and [(tert-butoxy)carbonyl]amino2,2-dimethylpropanoate according to Scheme 2. δH (500 MHz, CHLOROFORM-d)7.65 (1H, d, 4.1 Hz), 6.99 (1H, d, 4.1 Hz), 1.48 (9H, s), 1.35 (9H, s).

N-[(tert-Butoxy)carbonyl]pyridine-3-sulfonamido 2,2-dimethylpropanoate(110) is synthesised from 3-pyridine sulfonyl chloride, sodium hydrideand [(tert-butoxy)carbonyl]amino 2,2-dimethylpropanoate according toScheme 2. δH (500 MHz, CHLOROFORM-d) 9.16-9.26 (1H, m), 8.89 (1H, d, 4.4Hz), 8.36 (1H, d, 8.2 Hz), 7.54 (1H, dd, 8.2, 4.9 Hz), 1.42 (9H, s),1.37 (9H, s)

N-[(tert-Butoxy)carbonyl]pyridine-3-sulfonamido 2-methylpropanoate (111)is synthesised from 3-pyridine sulfonyl chloride, sodium hydride and[(tert-butoxy)carbonyl]amino 2-methylpropanoate according to Scheme 2.δH (500 MHz, CHLOROFORM-d) 9.21 (1H, d, 1.6 Hz), 8.89 (1H, dd, 4.7, 1.3Hz), 8.34 (1H, dd, 7.4, 1.4 Hz), 7.53 (1H, dd, 8.2, 4.9 Hz), 2.84 (1H,sept, 7.0 Hz), 1.42 (9H, s), 1.32 (6H, d, 6.9 Hz).

Example 5 Synthesis of Compounds 48 and 49

Preparation of ethyl(acetyloxy){[2-(methylsulfonyl)phenyl]sulfonyl}-carbamate (48)N-(Acetyloxy)-2-(methylsulfonyl)benzenesulfonamide

To a solution of tert-butyl(acetyloxy){[2-(methylsulfonyl)phenyl]sulfonyl}carbamate (0.5 g, 1.27mmol) in DCM (10 ml) is added trifluoroacetic acid (4 ml) and theresulting solution stirred at room temperature until complete removal ofthe BOC group is identified by LC-MS (2 hours). The crude reactionmixture is concentrated in vacuo and the resulting solid purified bytrituation with diethyl ether. (0.24 g, 64%), ¹H NMR (400 MHz, DMSO-d₆)δ ppm 10.63 (1H, br. s.), 8.28 (1H, dd, 7.5, 1.6 Hz), 8.21 (1H, dd, 7.5,1.6 Hz), 8.00-8.11 (2H, m), 3.47 (3H, s), 2.03 (3H, s).

Ethyl (acetyloxy){[2-(methylsulfonyl)phenyl]sulfonyl}-carbamate (48) isprepared according to Scheme 3. To a stirred solution ofN-(acetyloxy)-2-(methylsulfonyl)benzene-sulfonamide (0.085 g, 0.29 mmol)in dichloromethane (5 ml) is added triethylamine (50 μl, 0.35 mmol) andethyl chloroformate (30 μl, 0.32 mmol). The reaction mixture is stirredfor 3 hours before quenching with water (1 ml). The organics areseparated and dried over sodium sulfate, filtered and concentrated invacuo to yield the title compound which is purified by silica columnchromatography, eluting with 40% ethyl acetate: heptane. (60 mg, 57%),¹H NMR (250 MHz, CHLOROFORM-d) δ ppm 8.47-8.58 (1H, m), 8.34-8.45 (1H,m), 7.82-7.94 (2H, m), 4.25 (2H, q, 7.2 Hz), 3.42 (3H, s), 2.31 (3H, s),1.25 (3H, t, 7.2 Hz).

Preparation of ethyl (acetyloxy)[(2-bromophenyl)sulfonyl]carbamate (49)

Ethyl (acetyloxy)[(2-bromophenyl)sulfonyl]carbamate (49) is preparedfrom ethyl chloroformate and N-(acetyloxy)-2-bromobenzenesulfonamideaccording to Scheme 3. δH (250 MHz, CHLOROFORM-d) δ 8.23-8.37 (1H, m),7.74-7.85 (1H, m), 7.45-7.60 (2H, m), 4.21 (2H, q, 7.2 Hz), 2.34 (3H,s), 1.19 (3H, t, 7.2 Hz).

Example 6 Synthesis of Compound 52

To a solution of the compound formed in Scheme 2 in DCM is addedtrifluoroacetic acid. The reaction is stirred for 3 h at roomtemperature and concentrated in vacuo to yield the title compound as aclear, colourless gum. Purification is achieved by trituation fromheptane: ethyl acetate.

N-[(2,2-Dimethylpropanoyl)oxy]-4-methyl-N-{[2(methylsulfonyl)phenyl]sulfonyl}piperazine-1-carboxamide (52) isprepared from (2-methanesulfonylbenzene) sulfonamido2,2-dimethylpropanoate and N-methyl piperazine according to Scheme 5. Toa solution of the compound formed in Scheme 4 in DCM cooled to 0° C. isadded triethylamine (2 equiv). The solution is stirred at thistemperature for 5 minutes before phosgene (a 1.9M solution in toluene,1.5 equiv) is added. The solution is stirred for a further 45 minutesbefore quenching with water. The organics are dried over sodium sulfate,filtered and concentrated in vacuo. The crude carbamoyl chloride isredissolved in DCM and triethylamine (1.1 equiv) and a secondary amine(1 equiv) is added. The reaction is stirred at room temperature for 1 hbefore quenching with water. The organics are dried over sodium sulfate,filtered and concentrated in vacuo. Purification is achieved bytrituation with heptane:ethyl acetate. δH (500 MHz, CHLOROFORM-d) δ 8.42(2H, ddd, 12.3, 7.3, 2.1 Hz), 7.83-7.92 (2H, m), 3.75-3.87 (4H, m), 3.37(3H, s), 2.53 (4H, t, 4.1 Hz), 2.34 (3H, s), 1.25 (9H, s).

Example 7 Synthesis of Compounds 79-102

To a stirred solution of N-tert-butoxycarbonyl hydroxylamine (1 equiv)and a carboxylic acid (1 equiv) in DCM (10 vol) is added EDCl.HCl (1equiv). The reaction mixture is stirred at room temperature untilcomplete consumption of the starting material is observed by tlc. Thereaction mixture is washed with water (2×10 vol), dried over sodiumsulfate, filtered and concentrated in vacuo. The crude material ispurified by column chromatography eluting with heptane: ethyl acetate.

To a solution of tert-butyl N-hydroxycarbamate (1 equiv) in THF (20 vol)is added diphosgene (0.48 equiv) followed by pyridine (1 equiv)dropwise. The reaction mixture is stirred until all starting material isconsumed (monitored by tlc), filtered and concentrated in vacuo. Theresidue is dissolved in DCM (10 vol) and added drop wise to a solutionof amine (1 equiv), and triethylamine (1 equiv per basic centre incompound) in DCM (10 vol) at 0° C. The reaction mixture is stirred atroom temperature (reaction progress monitored by tlc), before beingwashed with water (2×10 vol) and re-extracted with further aliquots ofDCM (20 vol). The crude product is dried over sodium sulfate, filteredand concentrated in vacuo. The compound is purified directly by eithersilica column chromatography eluting with heptane: ethyl acetate or DCM:methanol followed by trituration where necessary.

To a solution of tert-butyl N-hydroxycarbamate (1 equiv) in THF (4 vol)and pyridine (1 equiv) at 0° C. is added para-nitrophenyl chloroformate(1 equiv) in THF (2.5 vol) drop wise. The reaction mixture is stirreduntil all starting material is consumed (monitored by tlc) before beingfiltered and the amine (1 equiv) is added. The reaction mixture isstirred at room temperature (reaction progress monitored by tlc) andconcentrated in vacuo. Compounds without basic centres are dissolved inDCM and washed with NaHCO₃ solution (2×10 vol) before being dried oversodium sulfate, filtered and concentrated in vacuo. The compound ispurified directly by either silica column chromatography eluting withheptane: ethyl acetate or DCM: methanol followed by trituration wherenecessary or reverse phase preparative HPLC.

To a solution of tert-butyl N-hydroxycarbamate (0.9 equiv) in DCM (10vol) is added carbonyldiimidazole (1 equiv). The reaction is stirred atroom temperature for 1 hour when the amine (1 equiv) is added. Thereaction mixture is stirred at room temperature until starting materialis consumed (monitored by tlc) and washed with water (2×5 vol) beforebeing dried over sodium sulfate, filtered and concentrated in vacuo. Thecompound is purified directly by either silica column chromatographyeluting with heptane: ethyl acetate or DCM: methanol

To a solution of an alcohol (1 equiv) in THF (10 vol) cooled to 5° C. issequentially added a 20% solution of phosgene in toluene (1 equiv) andpyridine (1 equiv). The reaction is stirred for 5 minutes beforeaddition of tert-butyl N-hydroxycarbamate (1 equiv) and pyridine (1equiv). Stirring is continued at room temperature until all startingmaterial is consumed (monitored by tlc) before the reaction mixture isfiltered through Celite™ and the resulting organics concentrated invacuo. The crude reaction is diluted with diethyl ether (20 vol), washedwith 0.1N HCl (5 vol) and water (5 vol), dried over sodium sulfate,filtered and concentrated in vacuo and purified by either silica columnchromatography eluting with heptane: ethyl acetate or reverse phasepreparative HPLC.

To a solution of N,O-disubstituted hydroxylamine (1 equiv) in DCM (20vol) and triethylamine (1 equiv) is added dimethylaminopyridine (0.1equiv) and a sulfonyl chloride (1 equiv). The reaction mixture isstirred at room temperature until complete consumption of the sulfonylchloride is observed by tlc, whereupon the reaction mixture is quenchedby the addition of water (10 vol) and extracted into DCM (10 vol). Thecombined organics are washed with water (10 vol), dried over sodiumsulfate, filtered and concentrated in vacuo and either used directlywithout additional purification or purified directly by either silicacolumn chromatography eluting with heptane: ethyl acetate or reversephase preparative HPLC.

Preparation of N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido (2S)-2-{[(tert butoxy)carbonyl](methyl)amino}-4-methylpentanoate (79)

[(tert-Butoxy)carbonyl]amino(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}-4-methylpentanoate isprepared from(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}-4-methylpentanoic acid andN-tert-butoxycarbonyl hydroxylamine according to Scheme 6. The compoundexists as rotomers and is reported as such. (1.8 g, 58%), ¹H NMR (500MHz, CHLOROFORM-d) δ ppm 7.49-8.06 (1H, m), 4.75-5.10 (1H, m), 2.86 (3H,d, 7.8 Hz), 1.66-1.88 (2H, m), 1.54-1.64 (1H, m), 1.50 (9H, s), 1.47(9H, d, 3.7 Hz), 0.96 (6H, dd, 10.7, 6.6 Hz).

N-[(tert-Butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido(2S)-2-{[(tert butoxy)carbonyl](methyl)amino}-4-methylpentanoate (79) issynthesised from 2-methanesulfonylbenzene sulfonyl chloride and[(tert-butoxy)carbonyl]amino(25)-2-{[(tert-butoxy)carbonyl](methyl)amino}-4-methylpentanoateaccording to Scheme 11. (0.51 g, 63%), ¹H NMR (500 MHz, CHLOROFORM-d) δppm 8.34-8.48 (2H, m), 7.80-7.90 (2H, m), 4.94-5.31 (1H, m), 3.42 (3H,d, 9.3 Hz), 2.77-2.92 (3H, m), 1.73-1.93 (2H, m), 1.58-1.68 (1H, m),1.47 (9H, d, 6.4 Hz), 1.41 (9H, s), 0.98 (6H, t, 7.4 Hz).

Preparation of N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido (2R)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanoate (80)

[(tert-Butoxy)carbonyl]amino(2R)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanoate is prepared from(2R)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanoic acid andN-tert-butoxycarbonyl hydroxylamine according to Scheme 6. The compoundexists as rotomers and is reported as such. (0.95 g, 60%), ¹H NMR (500MHz, CHLOROFORM-d) δ ppm 7.81-7.95 (1H, m), 4.60-5.04 (1H, m), 2.85-2.93(3H, m), 1.40-1.54 (18H, m), 1.22-1.33 (3H, m).

N-[(tert-Butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido(2R)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanoate (80) issynthesised from 2-methanesulfonyl benzene sulfonyl chloride and[(tert-butoxy)carbonyl]amino (2R)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanoate according to Scheme 11. (0.71 g, 44%),¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.23-8.50 (2H, m), 7.78-7.99 (2H,m), 4.79-5.34 (1H, m), 3.39-3.51 (3H, m), 2.59-2.95 (3H, m), 1.47 (9H,s), 1.41 (9H, s), 1.27 (3H, t, 7.2 Hz).

Preparation of N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido (2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanoate (81)

[(tert-Butoxy)carbonyl]amino(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}-propanoate is preparedfrom (2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanoic acid andN-tert-butoxycarbonyl hydroxylamine according to Scheme 6. (0.96 g,61%), The compound exists as rotomers and is reported as such. ¹H NMR(500 MHz, CHLOROFORM-d) δ ppm 7.73-7.89 (1H, m), 4.61-5.04 (1H, m),2.86-2.96 (3H, m), 1.41-1.53 (21H, m).

N-[(tert-Butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanoate (81) issynthesised from 2-methanesulfonyl benzene sulfonyl chloride[(tert-butoxy)carbonyl]amino(25)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanoate according toScheme 11. (0.03 g, 18%), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.21-8.53(2H, m), 7.73-8.02 (2H, m), 4.81-5.40 (1H, m), 3.36-3.51 (3H, m),2.60-2.98 (3H, m), 1.47 (9H, s), 1.33-1.44 (12H, m).

Preparation of N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido 2-{[(tertbutoxy)carbonyl](methyl)amino}acetate (82)

[(tert-Butoxy)carbonyl]amino2-{[(tert-utoxy)carbonyl](methyl)amino}acetate is prepared from{[(tert-butoxy)carbonyl](methyl)amino}acetate and N-tert-butoxycarbonylhydroxylamine according to Scheme 6. The compound exists as rotomers andis reported as such. (1.5 g, 93%), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm7.92 (1H, d, m), 4.03-4.23 (2H, m), 2.95-3.01 (3H, m), 1.41-1.54 (18H,m).

N-[(tert-Butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido2-{[(tert-butoxy)carbonyl](methyl)amino}acetate (82) is synthesised from2-methanesulfonyl benzene sulfonyl chloride and[(tert-butoxy)carbonyl]amino2-{[(tert-butoxy)carbonyl](methyl)amino}-acetate according to Scheme 11.(1.3 g, 51%), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.48 (1H, dd, 7.5,1.5 Hz), 8.35-8.44 (1H, m), 7.81-7.93 (2H, m), 3.90-4.63 (2H, m), 3.42(3H, d, J=2.0 Hz), 2.97 (3H, d, 14.2 Hz), 1.41-1.50 (18H, m)

Preparation of N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido(25)-2-{[(tert-butoxy)carbonyl](methyl)amino}-3-methylbutanoate (83)

[(tert-Butoxy)carbonyl]amino(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}-3-methylbutanoate isprepared from(25)-2-{[(tert-butoxy)carbonyl](methyl)amino}-3-methylbutanoate andN-tert-butoxycarbonyl hydroxylamine according to Scheme 6. The compoundexists as rotomers and is reported as such. (1.18 g, 42%), ¹H NMR (500MHz, CHLOROFORM-d) δ ppm 7.50-8.11 (1H, m), 4.02-4.94 (1H, m), 3.49-3.50(3H, m), 2.07-2.41 (1H, m), 1.37-1.55 (18H, m), 0.83-1.17 (6H, m).

N-[(tert-Butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}-3-methylbutanoate (83) issynthesised from 2-methanesulfonyl benzene sulfonyl chloride[(tert-butoxy)carbonyl]amino(25)-2-{[(tert-butoxy)carbonyl]-(methyl)amino}-3-methylbutanoateaccording to Scheme 11. 0.68 g, 68%), ¹H NMR (250 MHz, CHLOROFORM-d) δppm 8.31-8.50 (2H, m), 7.77-7.97 (2H, m), 4.25-5.02 (1H, m), 3.31-3.47(3H, m), 2.79-2.93 (3H, m), 2.21-2.41 (1H, m), 1.36-1.52 (18 H, m),1.03-1.12 (3H, m), 0.91-1.00 (3H, m)

Preparation ofN-[(tert-butoxy)carbonyl][(4-chlorophenyl)methane]sulfonamido2,2-dimethylpropanoate (84)

N-[(tert-Butoxy)carbonyl][(4-chlorophenyl)methane]sulfonamido 2,2dimethyl propanoate (84) is prepared from(4-chlorophenyl)methanesulfonyl chloride and[(tert-butoxy)carbonyl]amino 2,2-dimethylpropanoate according to Scheme11. (0.4 g, 32%), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.33-7.43 (4H,m), 4.56-5.04 (2H, m), 1.55 (9H, s), 1.29 (9H, s).

Preparation of N-[(benzyloxy)carbonyl](2-methanesulfonylbenzene)sulfonamido 2,2-dimethylpropanoate (85) [(Benzyloxy)carbonyl]amino2,2-dimethylpropanoate

To a solution of benzyl hydroxycarbamate (1 g, 5.98 mmol) in DCM (20 ml)is added triethylamine (0.6 g, 5.98 mmol) and 2,2-dimethylpropanoylchloride (0.74 ml, 5.98 mmol). After 2 hours the reaction mixture isquenched by the addition of water (10 ml) and the organics are extractedinto DCM (2×20 ml), dried over sodium sulfate, filtered and concentratedin vacuo to yield the title compound as a yellow oil which is usedwithout any further purification. (1.6 g, 100%), ¹H NMR (500 MHz,CHLOROFORM-d) δ ppm 8.02 (1H, br. s.), 7.29-7.43 (5H, m), 5.22 (2H, s),1.30 (9H, s).

N-[(Benzyloxy)carbonyl](2-methanesulfonylbenzene)sulfonamido2,2-dimethylpropanoate (85) is prepared from2-methylsulfonylbenzenesulfonyl chloride and [(benzyloxy)carbonyl]amino2,2-dimethylpropanoate according to Scheme 11. (0.9 g, 15%), ¹H NMR (500MHz, CHLOROFORM-d) δ ppm 8.42 (1H, dd, 8.0, 0.9 Hz), 8.35 (1H, dd, 7.9,1.3 Hz), 7.83 (1H, td, 7.6, 1.3 Hz), 7.72 (1H, td, 7.7, 1.3 Hz),7.30-7.36 (3H, m), 7.21 (2H, dd, 7.4, 1.9 Hz), 5.15 (2H, d, 19.7 Hz),3.32 (3H, s), 1.32 (9H, s).

Preparation of N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido N,N-dimethylcarbamate (86)

[(tert-Butoxy)carbonyl]amino N,N-dimethylcarbamate is prepared fromtert-butyl N-hydroxycarbamate and dimethyl carbamoyl chloride accordingto Scheme 1. (2.4 g, 78%), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.82(1H, br. s.), 3.02 (3H, s), 2.98 (3H, s), 1.49 (9H, s)

N-[(tert-Butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido-N,N-dimethylcarbamate (86) is prepared from [(tert-butoxy)carbonyl]aminoN,N-dimethylcarbamate and 2-methylsulfonylbenzenesulfonyl chlorideaccording to Scheme 11. (0.45 g, 42%), ¹H NMR (500 MHz, CHLOROFORM-d) δppm 8.54-9.01 (1H, m), 8.32-8.44 (1H, m), 7.76-7.90 (2H, m), 3.42 (3H,s), 3.09 (3H, s), 3.03 (3H, s), 1.41 (9H, s).

Alternatively,N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)-sulfonamido-N,N-dimethylcarbamate (86) is prepared via the following method:

A solution of [(tert-butoxy)carbonyl]amino N,N-dimethylcarbamate (1 g,4.9 mmol) in THF (5 ml) is added dropwise to a stirred solution ofsodium hydride (60% dispersion in oil, 0.24 g, 5.2 mmol) in THF (25 ml).Stirring is continued for 30 minutes, whereupon2-methylsulfonylbenzenesulfonyl chloride (1.35 g, 5.4 mmol) is added.The reaction mixture is stirred at room temperature for 3 hours afterwhich time tlc (1:1 heptane:ethyl acetate) showed no starting materialremained. The reaction mixture is quenched by the addition of water (5ml) and extracted into diethyl ether (2×20 ml). The combined organicsare dried over sodium sulfate, filtered and concentrated in vacuo toyield the desired material, which is purified by silica columnchromatography eluting with heptane: ethyl acetate (1:1; v:v) (1.1 g,53%).

Preparation of N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamidoN,N-dimethylcarbamate (87)

N-[(tert-Butoxy)carbonyl](2-bromobenzene)sulfonamidoN,N-dimethylcarbamate (87) is prepared from [(tert-butoxy)carbonyl]aminoN,N-dimethylcarbamate and 2-bromobenzenesulfonyl chloride according toScheme 11. (0.655 g, 37%), ¹H NMR (250 MHz, CHLOROFORM-d) δ ppm8.25-8.37 (1H, m), 7.71-7.82 (1H, m), 7.44-7.55 (2H, m), 3.02 (3H, s),2.99 (3H, s), 1.50 (9H, s).

Preparation of N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido morpholine-4-carboxylate (88)

[(tert-Butoxy)carbonyl]amino morpholine-4-carboxylate is prepared frommorpholine-4-carbonyl chloride and according to Scheme 1. (1.71 g,105%), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.78 (1H, s), 3.66-3.78 (4H,m), 3.46-3.65 (4H, m), 1.50 (9H, s).

N-[(tert-Butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamidomorpholine-4-carboxylate (88) is prepared from[(tert-butoxy)carbonyl]amino morpholine-4-carboxylate and2-methylsulfonylbenzenesulfonyl chloride according to Scheme 11. (1.12g, 61%), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.54-8.66 (1H, m),8.32-8.43 (1H, m), 7.74-7.91 (2H, m), 3.49-3.86 (8H, m), 3.41 (3H, s),1.43 (9H, s).

Preparation N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido 4-acetylpiperazine-1-carboxylate (89)

[(tert-Butoxy)carbonyl]amino 4-acetylpiperazine-1-carboxylate isprepared according to Scheme 7. To a solution of tert-butylN-hydroxycarbamate (1.0 g, 7.44 mmol) in THF (20 ml) is added diphosgene(0.44 ml, 3.57 mmol) followed by pyridine (0.6 ml, 7.44 mmol) drop wise.The reaction mixture is stirred for 1 hour at room temperature, filteredand concentrated. The residue is dissolved in DCM (10 ml) and added dropwise to a solution of 4-acetylpiperazine (0.95 g, 7.44 mmol), intriethylamine (1.0 ml, 7.44 mmol) and DCM (10 ml) at 0° C. The reactionmixture is stirred at room temperature for 18 hours. The reactionmixture is washed with water (2×2 ml), dried over sodium sulfate,filtered and concentrated in vacuo. The title compound is purifieddirectly by silica column chromatography eluting with ethyl acetateyielding the title compound as a white solid. (0.75 g, 35%), ¹H NMR (500MHz, CHLOROFORM-d) δ ppm 7.70 (1H, br. s.), 3.24-3.68 (8H, m), 2.06 (3H,s), 1.43 (9H, s).

N-[(tert-Butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido4-acetylpiperazine-1-carboxylate (89) is prepared from[(tert-butoxy)carbonyl]amino 4-acetylpiperazine-1-carboxylate and2-methylsulfonylbenzenesulfonyl chloride according to Scheme 11. (0.89g, 70%), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.45-8.62 (1H, m),8.23-8.37 (1H, m), 7.72-7.83 (2H, m), 3.35-3.75 (8H, m), 3.32 (3H, s),2.04-2.10 (3H, m), 1.35 (9H, s)

Preparation of N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido N-cyclohexyl-N-methylcarbamate (90)

tert-Butyl N-{[cyclohexyl(methyl)carbamoyl]oxy}carbamate is preparedaccording to Scheme 8.

To a solution of tert-butyl N-hydroxycarbamate (2.0 g, 15.0 mmol) in THF(8 ml) and pyridine (1.2 ml, 15.0 mmol)) at 0° C. is addedpara-nitrophenyl chloroformate (3.0 g, 15.0 mmol) in THF (7.5 ml) dropwise. The reaction mixture is stirred for 1 hour before being filteredand N-methylcyclohexanamine (1.96 ml, 15.0 mmol) added. The reactionmixture is stirred at room temperature for 18 hours and concentrated invacuo. Dissolved in DCM (20 ml) and washed with NaHCO₃ solution (2×5 ml)before being dried over sodium sulfate, filtered and concentrated invacuo, the title compound is purified directly by silica columnchromatography eluting with DCM: methanol and taken to the next stepwith no further purification (0.81 g).

N-[(tert-Butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamidoN-cyclohexyl-N-methylcarbamate (90) is prepared from2-ethylsulfonylbenzenesulfonyl chloride and tert-butylN-{[cyclohexyl(methyl)carbamoyl]oxy}carbamate according to Scheme 11.(0.44 g, 6% over two steps), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm8.52-8.65 (1H, m), 8.23-8.36 (1H, m), 7.69-7.82 (2H, m), 3.79-4.00 (1H,m), 3.34 (3H, s), 2.86 (3H, s), 0.90-1.88 (19H, m).

Preparation of 1-N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido 4-tert-butyl piperazine-1,4-dicarboxylate (91)

1-[(tert-Butoxy)carbonyl]amino 4-tert-butyl piperazine-1,4-dicarboxylateis prepared from tert-butyl N-hydroxycarbamate and tert-butylpiperazine-1-carboxylate according to Scheme 8. (0.75 g, 35%), ¹H NMR(250 MHz, CHLOROFORM-d) δ ppm 7.76 (1H, s), 3.43-3.62 (8H, m), 1.50 (9H,s), 1.48 (9H, s).

1-N-[(tert-Butoxy)carbonyl](2-methanesulfonylbenzene) sulfonamido4-tert-butyl piperazine-1,4-dicarboxylate (91) is prepared from2-methylsulfonylbenzenesulfonyl chloride and1-[(tert-butoxy)carbonyl]amino 4-tert-butyl piperazine-1,4-dicarboxylateaccording to Scheme 11. (0.86 g, 57%), ¹H NMR (500 MHz, CHLOROFORM-d) δppm 8.52-8.67 (1H, m), 8.31-8.49 (1H, m), 7.76-7.96 (2H, m), 3.45-3.78(8H, m), 3.40 (3H, s), 1.48 (9H, s), 1.42 (9H, s).

Preparation of N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido N-(2-methoxyethyl) carbamate (92)

[(tert-Butoxy)carbonyl]amino N-(2-methoxyethyl)carbamate is preparedfrom tert-butyl N-hydroxycarbamate and (2-methoxyethyl)(methyl)amineaccording to Scheme 7. (0.58 g, 32%), ¹H NMR (500 MHz, CHLOROFORM-d) δppm 7.79 (1H, s), 3.46-3.64 (4H, m), 3.36 (3H, d, 4.4 Hz), 3.06 (3H, d,10.6 Hz), 1.50 (9H, s)

N-[(tert-Butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamidoN-(2-methoxyethyl) carbamate (92) is prepared from2-methylsulfonylbenzenesulfonyl chloride and[(tert-butoxy)carbonyl]amino N-(2-methoxyethyl)carbamate according toScheme 11 (0.58 g, 53%), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.63-8.73(1H, m), 8.29-8.42 (1H, m), 7.86 (2H, dd, 5.8, 3.2 Hz), 3.50-3.75 (4H,m), 3.43 (3H, d, 4.4 Hz), 3.38 (3H, d, 4.6 Hz), 3.14 (3H, d, 14.0 Hz),1.42 (9H, s).

Preparation of N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido N,N diethylcarbamate (93)

[(tert-Butoxy)carbonyl]amino N,N-diethylcarbamate is prepared fromtert-butyl N-hydroxycarbamate and diethyl carbamoyl chloride accordingto Scheme 1. (0.67 g, 39%), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.84(1H, br. s.), 3.33 (4H, q, 7.1 Hz), 1.48 (9H, s), 1.11-1.28 (6H, m).

N-[(tert-Butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido N,Ndiethylcarbamate (93) is prepared from [(tert-butoxy)carbonyl]aminoN,N-diethylcarbamate and 2-methylsulfonylbenzenesulfonyl chlorideaccording to Scheme 11. (0.47 g, 36%), ¹H NMR (500 MHz, CHLOROFORM-d) δppm 8.55-8.70 (1H, m), 8.29-8.36 (1H, m), 7.77-7.87 (2H, m), 3.18-3.52(7H, m), 1.35 (9H, s), 1.22 (3H, t, 7.1 Hz), 1.16 (3H, t, 7.0 Hz).

Preparation of N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido N-methoxy-N-methylcarbamate (94)

[(tert-Butoxy)carbonyl]amino N-methoxy-N-methylcarbamate is preparedfrom tert-butyl N-hydroxycarbamate and N-Methoxy-N-methylcarbamoylchloride according to Scheme 1. (2.48 g, 100%), ¹H NMR (500 MHz,CHLOROFORM-d) δ ppm 7.83 (1H, s), 3.76 (3H, s), 3.23 (3H, s), 1.48 (9H,s).

N-[(tert-Butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamidoN-methoxy-N-methylcarbamate (94) is prepared from[(tert-butoxy)carbonyl]amino N-methoxy-N-methylcarbamate and2-methylsulfonylbenzenesulfonyl chloride according to Scheme 11. ¹H NMR(500 MHz, CHLOROFORM-d) δ ppm 8.55-8.63 (1H, m), 8.34-8.42 (1H, m),7.81-7.88 (2H, m), 3.80 (3H, s), 3.42 (3H, s), 3.30 (3H, s), 1.42 (9H,s).

Preparation of tert-butylN-[(2-methanesulfonylbenzene)sulfonyl]-N-{[methyl(pyridin-3-ylmethyl)carbamoyl]oxy}carbamate (95)

tert-Butyl N-{[methyl(pyridin-3-ylmethyl)carbamoyl]oxy}carbamate isprepared from tert-butyl N-hydroxycarbamate andmethyl(pyridin-3-ylmethyl)amine according to Scheme 1. This material isused in the synthesis of tert-butylN-[(2-methanesulfonylbenzene)sulfonyl]-N-{[methyl(pyridin-3-ylmethyl)carbamoyl]oxy}carbamatewithout further purification (0.52 g).

tert-ButylN-[(2-methanesulfonylbenzene)sulfonyl]-N-{[methyl(pyridin-3-ylmethyl)carbamoyl]oxy}carbamate (95) is prepared from tert-butylN-{[methyl(pyridin-3-ylmethyl)carbamoyl]oxy}carbamate and2-methylsulfonylbenzenesulfonyl chloride according to Scheme 7. (0.26 g,7% over two steps), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.54-8.82 (3H,m), 8.28-8.46 (1H, m), 7.94-8.19 (1H, m), 7.80-7.94 (2H, m), 7.54 (1H,br. s.), 4.53-4.84 (2H, m), 3.42 (3H, s), 2.93-3.18 (3H, m), 1.44 (9H,s).

Preparation of tert-butyl2-{[2-(tert-butoxy)-2-oxoethyl][({N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido}oxy)carbonyl]amino}acetate(96)

tert-Butyl2-{[2-(tert-butoxy)-2-oxoethyl][({[(tert-butoxy)carbonyl]amino}oxy)carbonyl]amino}acetateis prepared from tert-butyl N-hydroxycarbamate and di-tert-butyl2,2′-iminodiacetate according to Scheme 9. (2.46 g, 59.7%), ¹H NMR (500MHz, CHLOROFORM-d) δ ppm 7.72 (1H, s), 4.08 (2H, s), 4.04 (2H, s),1.41-1.51 (27H, m).

tert-Butyl2-{[2-(tert-butoxy)-2-oxoethyl][({N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene) sulfonamido}oxy)carbonyl]amino}acetate (96) is preparedfrom tert-butyl2-{[2-(tert-butoxy)-2-oxoethyl][({[(tert-butoxy)carbonyl]amino}oxy)carbonyl]amino}acetateand 2-methylsulfonylbenzenesulfonyl chloride according to Scheme 11.(0.74 g, 13.6%), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.48-8.55 (1H, m),8.27-8.31 (1H, m), 7.71-7.80 (2H, m), 3.90-4.13 (4H, m), 3.33 (3H, s),1.42 (9H, s), 1.40 (9H, s), 1.34 (9H, s).

Preparation of 4-{[({N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido}oxy)carbonyl]oxy}oxane (97)

4-{[({[(tert-Butoxy)carbonyl]amino}oxy)carbonyl]oxy}oxane is preparedaccording to Scheme 9. To a solution of tetrahydropyran-4-ol (2 g, 19.6mmol) in THF (20 mL) cooled to 5° C. is sequentially added a 20%solution of phosgene in toluene (10.3 mL, 19.6 mmol) and pyridine (1.6mL, 19.6 mmol). The reaction is stirred for 5 minutes before addition oftert-butyl N-hydroxycarbamate (2.6 g, 19.6 mmol) and pyridine (1.6 mL,19.6 mmol). Stirring is continued for 30 minutes at room temperaturebefore the reaction mixture is filtered through Celite™ and theresulting organics concentrated in vacuo. The crude reaction is dilutedwith diethyl ether (50 mL), washed with 0.1N HCl (10 ml) and water (10ml), dried over sodium sulfate, filtered and concentrated in vacuo.Purification is achieved by silica gel column chromatography elutingwith heptane: ethyl acetate (1:1; v:v) to yield the title compound as aclear, colourless oil. (3.64 g, 71%), ¹H NMR (500 MHz, CHLOROFORM-d) δppm 7.78 (1H, s), 4.92 (1H, tt, 8.4, 4.0 Hz), 3.88-3.98 (2H, m), 3.55(2H, ddd, 11.8, 8.7, 3.1 Hz), 1.98-2.09 (2H, m), 1.80 (2H, m), 1.50 (9H,s).

4-{[({N-[(tert-Butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido}oxy)-carbonyl]oxy}oxane(97) is prepared from4-{[({[(tertbutoxy)carbonyl]amino}oxy)-carbonyl]oxy}oxane and2-methylsulfonylbenzenesulfonyl chloride according to Scheme 11. (0.5 g,27% yield), ¹H NMR (250 MHz, CHLOROFORM-d) δ ppm 8.36-8.49 (2H, m),7.83-7.90 (2H, m), 4.91-5.04 (1H, m), 3.87-4.02 (2H, m), 3.51-3.64 (2H,m), 3.43 (3H, s), 1.98-2.13 (2H, m), 1.74-1.94 (2H, m), 1.58 (9H, s).

Preparation of 4-{[({N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamido}oxy)carbonyl]-oxy}oxane (98)

4-{[({N-[(tert-Butoxy)carbonyl](2-bromobenzene)sulfonamido}oxy)carbonyl]oxy}oxane(98) is synthesised from 2-bromobenzene sulfonyl chloride and4-{[({[(tert-butoxy)carbonyl]amino}oxy)carbonyl]oxy}oxane according toScheme 11. (1.17 g, 77%), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.22-8.30(1H, m), 7.76-7.84 (1H, m), 7.47-7.57 (2H, m), 4.98-5.11 (1H, m),3.91-4.02 (2H, m), 3.52-3.64 (2H, m), 1.98-2.14 (2H, m), 1.73-1.93 (2H,m), 1.39 (9H, s).

Preparation of1-({[(tert-butoxy)carbonyl][(methoxycarbonyl)oxy]amino}sulfonyl)-2-methanesulfonylbenzene (99) 2-({[(Methoxycarbonyl)oxy]carbamoyl}oxy)-2-methylpropane

To a solution of tert-butyl N-hydroxycarbamate (1.4 g, 10.6 mmol) in DCM(10 ml) is added triethylamine (1.5 ml, 10.6 mmol) at 0° C. Methylchoroformate (814 μl, 10.6 mmol) is added drop wise. Reaction stirredfor 18 hours at room temperature before being washed with water (2×10ml), NaHCO₃ (2×10 ml), dried over magnesium sulfate and concentrated invacuo to give the title product as an oil. (1.76 g, 87%), ¹H NMR (500MHz, CHLOROFORM-d) δ ppm 7.71 (1H, br. s.), 3.92 (3H, s), 1.50 (9H, s).

1-({[(tert-Butoxy)carbonyl][(methoxycarbonyl)oxy]amino}sulfonyl)-2-methanesulfonylbenzene (99) is prepared from2-({[(methoxycarbonyl)oxy]-carbamoyl}oxy)-2-methylpropane according toScheme 11. (0.96 g, 60%), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.38-8.47(2H, m), 7.82-7.90 (2H, m), 3.99 (3H, s), 3.42 (3H, s), 1.40-1.47 (9H,m).

Preparation of1-({[(tert-butoxy)carbonyl]({[(2-methoxyethoxy)carbonyl]oxy})amino}sulfonyl)-2-methanesulfonylbenzene(100)1-{[({[(tert-Butoxy)carbonyl]amino}oxy)carbonyl]oxy}-2-methoxyethane

To a solution of tert-butyl N-hydroxycarbamate (1.5 g, 11.3 mmol) in DCM(50 ml) is added triethylamine (1.6 ml, 11.3 mmol) at 0° C.Chloro(2-methoxyethoxy)methanone (1.56 g, 11.3 mmol) is added dropwise.Reaction is stirred for 18 hours at room temperature before being washedwith water (2×10 ml), NaHCO₃ (2×10 ml), dried (MgSO₄) and concentratedin vacuo to give the title product as an oil. (0.67 g, 25%), ¹H NMR (500MHz, CHLOROFORM-d) δ ppm 7.74-8.46 (1H, m), 4.23-4.73 (2H, m), 3.45-3.84(2H, m), 3.34 (3H, s), 1.41 (9H, s).

1-({[(tert-Butoxy)carbonyl]({[(2-methoxyethoxy)carbonyl]oxy})amino}-sulfonyl)-2-methanesulfonylbenzene(100) is prepared from 1-{[({[(tert-butoxy)carbonyl]amino}oxy)carbonyl]oxy}-2-methoxyethane and 2-methylsulfonyl benzenesulfonylchloride according to Scheme 11. (0.59 g, 46%), ¹H NMR (500 MHz,CHLOROFORM-d) δ ppm 8.16-8.80 (2H, m), 7.54-8.02 (2H, m), 4.47-4.47 (2H,m), 3.66 (2H, d, 4.1 Hz), 3.41 (3H, s), 3.38 (3H, s), 1.42 (9H, s)

Preparation of1-({[(tert-butoxy)carbonyl]({[2-(2-methoxyethoxy)ethoxy]carbonyl}oxy)-amino}sulfonyl)-2-methanesulfonylbenzene(101)

1-(2-{[({[(tert-Butoxy)carbonyl]amino}oxy)carbonyl]oxy}ethoxy)-2-methoxyethaneis prepared from tert-butyl N-hydroxycarbamate and2-(2-methoxyethoxy)ethanol using 20% solution of phosgene in tolueneaccording to Scheme 10. (9.95 g, 82%), ¹H NMR (250 MHz, CHLOROFORM-d) δppm 7.88 (1H, s), 4.36-4.45 (2H, m), 3.72-3.80 (2H, m), 3.61-3.68 (2H,m), 3.51-3.58 (2H, m), 3.37 (3H, s), 1.49 (9H, s).

1-({[(tert-Butoxy)carbonyl]({[2-(2-methoxyethoxy)ethoxy]carbonyl}oxy)-amino}sulfonyl)-2-methanesulfonylbenzene(101) is prepared from1-(2-{[({[(tert-butoxy)carbonyl]amino}oxy)carbonyl]oxy}ethoxy)-2-methoxyethaneand 2-methylsulfonyl benzene sulfonyl chloride according to Scheme 11.(2.72 g, 70%), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.40 (2H, ddd, 12.7,7.5, 1.5 Hz), 7.86 (2H, m), 4.37-4.56 (2H, m), 3.71-3.85 (2H, m),3.62-3.71 (2H, m), 3.50-3.60 (2H, m), 3.43 (3H, s), 3.39 (3H, s), 1.43(9H, s).

Preparation of1-({[(tert-butoxy)carbonyl]({[(1,3-diethoxypropan-2-yl)oxy]carbonyl}oxy)-amino}sulfonyl)-2-methanesulfonylbenzene(102)

2-{[({[(tert-Butoxy)carbonyl]amino}oxy)carbonyl]oxy}-1,3-diethoxypropaneis prepared from tert-butyl N-hydroxycarbamate and1,3-diethoxypropan-2-ol using 20% solution of phosgene in tolueneaccording to Scheme 10. (10.37 g, 85%), ¹H NMR (500 MHz, CHLOROFORM-d) δppm 7.73 (1H, s), 5.03 (1H, quin, 5.2 Hz), 3.64 (4H, dd, 5.1, 2.7 Hz),3.48-3.57 (4H, m), 1.50 (9H, s), 1.19 (6H, t, 7.0 Hz).

1-({[(tert-Butoxy)carbonyl]({[(1,3-diethoxypropan-2-yl)oxy]carbonyl}oxy)-amino}sulfonyl)-2-methanesulfonylbenzene(102) is prepared from2-{[({[(tert-butoxy)carbonyl]amino}oxy)carbonyl]oxy}-1,3-diethoxypropaneand 2-methylsulfonyl benzene sulfonyl chloride according to Scheme 11.(2.3 g, 47%), ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.39 (2H, ddd, 12.2,7.5, 1.5 Hz), 7.84 (2H, m), 5.06 (1H, quin, 5.1 Hz), 3.68 (4H, t, 4.9Hz), 3.48-3.61 (4H, m), 1.43 (9H, s), 1.27 (3H, t, 7.2 Hz), 1.19 (3H, t,6.9 Hz).

Example 8 HNO Production Via N₂O Quantification

Nitrous oxide is produced via the dimerization and dehydration of HNO,and is the most common marker for HNO production (Fukuto, J. M. et al.,Chem. Res. Toxicol. 2005, 18, 790-801). HNO, however, can also bepartially quenched by oxygen to yield a product that does not produceN₂O (see Mincione, F. et al., J. Enzyme Inhibition 1998, 13, 267-284;and Scozzafava, A. et al., J. Med. Chem. 2000, 43, 3677-3687.) UsingAngeli's salt (AS) as a benchmark, the relative amounts of N₂O releasedfrom compounds are examined via gas chromatography (GC) headspaceanalysis.

The ability of compounds to donate HNO is assessed. Results are providedin Table 3. N₂O results are reported relative to Angeli's salt. Alldecompositions are carried out at 37° C. under argon.

TABLE 3 % N₂O % N₂O % N₂O % N₂O⁹ Decomp. Compound DI⁶ pH 7.4⁷ pH 10.3⁸esterase Time¹⁰ 1 29 1 <3 h 2 32 1 <3 h 3 56 4 <3 h 4 59 5 <3 h 5 48 <3h 6 2 <3 h 7 7 <3 h 8 2 <3 h 9 80 15 <3 h 10 98 39 <3 h 11 31 12 <3 h 1237 1 <3 h 13 9 <3 h 14 48 6 <3 h 15 7 <3 h 18 4 <3 h 19 35 <2 h (20 min)20 23 <3 h 21 39 <3 h 22 71 <2 h (20 min) 23 56 56 57 <3 h (40 min) 2423 <3 h (30 min) 25 13 <3 h 26 13 <3 h 27 57 <3 h 28 17 44 <3 h 29 21 5283 <3 h 30 3 8 <3 h 31 5 <20 h  32 0 >20 h  33 1 33 <20 h  36 7 67 <2 h37 4 85 <3 h 38 3 37 73 <3 h 40 0 <3 h ⁶Compound incubated in DI water.⁷Compound incubated in PBS buffer, pH 7.4. ⁸Compound incubated in pH.10.3 carbonate buffer. ⁹Compound incubated in PBS buffer, pH 7.4 with2-4 mg added esterase. ¹⁰Time required for complete decomposition ofcompound incubated in PBS buffer, pH 7.4 as determined by HPLC; whenmeasured, an approximate half-life is reported in parentheses.

Example 8A HNO Production Via N₂O Quantification

Compounds are tested in the assay described in Example 7, with thefollowing modification. Test compounds are assessed with and alsowithout the addition of Pig Liver Esterase (PLE) at 37° C. for 90minutes in PBS buffer at pH 7.4. Certain compounds described herein aretested and show detectable levels of HNO. Certain compounds describedherein exhibit enhanced HNO production in the presence of PLE. Compoundstability is also determined by assessing the half-life of the compoundsin PBS at 37° C. at pH 7.4 with and without the addition of PLEaccording to methods known in the art, e.g., in PCT publication No.PCT/US2007/0067 10.

Example 9 In Vitro Model to Determine Ability of Compounds orPharmaceutical Compositions to Treat, Prevent and/or Delay Onset and/orDevelopment of a Disease or Condition Cardiovascular Diseases orConditions

In vitro models of cardiovascular disease can also be used to determinethe ability of any of the compounds and pharmaceutical compositionsdescribed herein to treat, prevent and/or delay the onset and/or thedevelopment of a cardiovascular disease or condition in an individual.An exemplary in vitro model of heart disease is described below.

In-vitro models could be utilized to assess vasorelaxation properties ofthe compounds and pharmaceutical compositions. Isometric tension inisolated rat thoracic aortic ring segment can be measured as describedpreviously by Crawford, J. H. et al., Blood 2006, 107, 566-575. Uponsacrifice, aortic ring segments are excised and cleansed of fat andadhering tissue. Vessels are then cut into individual ring segments (2-3mm in width) and suspended from a force-displacement transducer in atissue bath. Ring segments are bathed at 37° C. in abicarbonate-buffered, Krebs-Henseleit (K-H) solution of the followingcomposition (mM): NaCl 118; KCl 4.6; NaHCO3 27.2; KH2PO4 1.2; MgSO4 1.2;CaCl2 1.75; Na2EDTA 0.03; and glucose 11.1 and perfused continuouslywith 21% O2/5% CO2/74% N2. A passive load of 2 g is applied to all ringsegments and maintained at this level throughout the experiments. At thebeginning of each experiment, indomethacin-treated ring segments aredepolarized with KCl (70 mM) to determine the maximal contractilecapacity of the vessel. Rings are then washed extensively and allowed toequilibrate. For subsequent experiments, vessels are submaximallycontracted (50% of KCl response) with phenylephrine (PE, 3×10⁻⁸-10⁻⁷ M),and L-NMMA, 0.1 mM, is also added to inhibit eNOS and endogenous NOproduction. After tension development reaches a plateau, compounds orpharmaceutical compositions are added cumulatively to the vessel bathand effects on tension monitored.

In vitro models can be utilized to determine the effects of thecompounds and pharmaceutical compositions in changes in developed forceand intracellular calcium in heart muscles. Developed force andintracellular calcium can be measured in rat trabeculae from normal ordiseased (i.e. rats with congestive heart failure or hypertrophy) asdescribed previously (Gao W. D. et al., Circ. Res. 1995, 76:1036-1048).Rats (Sprague-Dawley, 250-300 g) are used in these experiments. The ratsare anesthetized with pentobarbital (100 mg/kg) via intra-abdominalinjection, the heart exposed by mid-sternotomy, rapidly excised andplaced in a dissection dish. The aorta is cannulated and the heartperfused retrograde (˜15 mM/min) with dissecting Krebs-Henseleit (H-K)solution equilibrated with 95% O₂ and 5% CO2. The dissecting K-Hsolution is composed of (mM): NaCl 120, NaHCO3 20, KCl 5, MgCl 2 1.2,glucose 10, CaCl2 0.5, and 2,3-butanedione monoximine (BDM) 20, pH7.35-7.45 at room temperature (21-22° C.). Trabeculae from the rightventricle of the heart are dissected and mounted between a forcetransducer and a motor arm and superfused with normal K-H solution (KCl,5 mM) at a rate of ˜10 ml/min and stimulated at 0.5 Hz. Dimensions ofthe muscles are measured with a calibration reticule in the ocular ofthe dissection microscope (×40, resolution ˜10 μm).

Force is measured using a force transducer system and is expressed inmillinewtons per square millimeter of cross-sectional area. Sarcomerelength is measured by laser diffraction. Resting sarcomere length is setat 2.20-2.30 μm throughout the experiments.

Intracellular calcium is measured using the free acid form of fura-2 asdescribed in previous studies (Gao et al., 1994; Backx et al., 1995; Gaoet al., 1998). Fura-2 potassium salt is microinjected iontophoreticallyinto one cell and allowed to spread throughout the whole muscle (via gapjunctions). The tip of the electrode (˜0.2 μm in diameter) is filledwith fura-2 salt (1 mM) and the remainder of the electrode is filledwith 150 mM KCl. After a successful impalement into a superficial cellin non-stimulated muscle, a hyperpolarizing current of 5-10 nA is passedcontinuously for ˜15 min. Fura-2 epifluorescence is measured by excitingat 380 and 340 nm. Fluorescent light is collected at 510 nm by aphotomultiplier tube. The output of photomultiplier is collected anddigitized. Ryanodine (1.0 μM) is used to enable steady-state activation.After 15 min of exposure to ryanodine, different levels of tetanizationsare induced briefly (˜4-8 seconds) by stimulating the muscles at 10 Hzat varied extracellular calcium (0.5-20 mM). All experiments areperformed at room temperature (20-22° C.).

Diseases or Conditions Implicating Ischemia/Reperfusion

In vitro models can also be used to determine the ability of any of thecompounds and pharmaceutical compositions described herein to treat,prevent and/or delay the onset and/or the development of a disease orcondition implicating ischemia/reperfusion injury in an individual.

Cancer

Antitumor activities of the compounds described herein can be assessedusing in vitro proliferation assays of tumor cells using well-knownmethods, such as described in Norris A. J. et al. Intl. J. Cancer 2008,122:1905-1910.

Cells of an appropriate cell line, e.g. human breast cancer cell lineMCF-7, are seeded in 96-well tissue culture microtiter plates at 4000cells per well for an overnight incubation. Serial 10-fold dilutions oftest compounds are added, and the cells are incubated for 72 h. The cellviability is determined using the CellTiter-Glo™ Luminescent CellViability Assay (Promega; Madison, Wis.). IC₅₀ is measured as theconcentration of drug required for inhibiting cell growth by 50%.

Example 10 In Vivo and/or Ex Vivo Models to Determine Ability ofCompounds and Pharmaceutical Compositions to Treat, Prevent and/or DelayOnset and/or Development of a Disease or Condition CardiovascularDiseases or Condition

In vivo models of cardiovascular disease can also be used to determinethe ability of any of the compounds and pharmaceutical compositionsdescribed herein to treat, prevent and/or delay the onset and/or thedevelopment of a cardiovascular disease or condition in an individual.An exemplary animal model of heart disease is described below.

In vivo cardiovascular effects obtained with a compound orpharmaceutical composition may be assessed in a control (normal) dog.The study is conducted in adult (25 kg) mongrel (male) dogs chronicallyinstrumented for conscious hemodynamic analysis and blood sampling, aspreviously described (Katori, T. et al., Circ. Res. 2005, 96, 234-243.).Micromanometer transducers in the left ventricle provide pressure, whileright atrial and descending aortic catheters provide fluid-pressures andsampling conduits. Endocardial sonomicrometers (anteriorposterior,septal-lateral) measure short-axis dimensions, a pneumatic occluderaround the inferior vena cave facilitated pre-load manipulations forpressure-relation analysis. Epicardial pacing leads are placed on theright atrium, and another pair is placed on the right ventricle freewall linked to a permanent pacemaker to induce rapid pacing-cardiacfailure. After 10 days of recovery, animals are evaluated at baselinesinus rhythm and with atrial pacing (120-160 bpm). Measurements includeconscious hemodynamic recordings for cardiac mechanics.

Compounds described herein are administrated to a healthy control dog atthe dose of 1-5 μg/kg/min and the resulting cardiovascular data isobtained.

Demonstration that a compound described herein improves cardiachemodynamics in hearts with congestive failure: After completingprotocols under baseline conditions, congestive heart failure is inducedby tachypacing (210 bpm×3 weeks, 240 bpm×1 week), as previouslydescribed (Katori, T. et al., Circ. Res. 2005, 96: 234-243.). Briefly,end-diastolic pressure and dP/dt_(max) are measured weekly to monitorfailure progression. When animals demonstrate a rise in EDP more than2×, and dP/dt_(max) of >50% baseline, they are deemed ready forcongestive heart failure studies.

The values for test compounds and pharmaceutical compositions areobtained after 15 min continuous i.v. infusion (2.5 or 1.25 μg/kg/min)in control and heart failure preparations, respectively, both in theabsence and in the presence of volume restoration. For comparison, thesame hemodynamic measurements are obtained with AS in heart failurepreparations.

Diseases or Conditions Implicating Ischemia/Reperfusion

Ex-vivo models of ischemia/reperfusion can also be used to determine theability of any of the compounds described herein to treat, preventand/or delay the onset and/or the development of a disease or conditionimplicating ischemia/reperfusion injury in an individual. An exemplaryex vivo model of ischemia/reperfusion injury is described below.

Male Wistar rats are housed in identical cages and allowed access to tapwater and a standard rodent diet ad libitum. Each animal is anesthetizedwith 1 g/kg urethane i.p. 10 min after heparin (2,500 U, i.m.)treatment. The chest is opened, and the heart is rapidly excised, placedin ice-cold buffer solution and weighed. Isolated rat hearts areattached to a perfusion apparatus and retrogradely perfused withoxygenated buffer solution at 37° C. The hearts are instrumented aspreviously described in Rastaldo et al., Am. J. Physiol. 2001, 280,H2823-H2832, and Paolocci et al., Am. J. Physiol. 2000, 279,H1982-H1988. The flow is maintained constant (approximately 9 mL/min/gwet weight) to reach a typical coronary perfusion pressure of 85-90mmHg. A constant proportion of 10% of the flow rate is applied by meansof one of two perfusion pumps (Terumo, Tokyo, Japan) using a 50 mLsyringe connected to the aortic cannula. Drug applications are performedby switching from the syringe containing buffer alone to the syringe ofthe other pump containing the drug (compound or pharmaceuticalcomposition described herein) dissolved in a vehicle at a concentration10× to the desired final concentration in the heart. A small hole in theleft ventricular wall allows drainage of the thebesian flow, and apolyvinyl-chloride balloon is placed into the left ventricle andconnected to an electromanometer for recording of left ventricularpressure (LVP). The hearts are electrically paced at 280-300 bpm andkept in a temperature-controlled chamber (37° C.). Coronary perfusionpressure (CPP) and coronary flow are monitored with a secondelectromanometer and an electromagnetic flow-probe, respectively, bothplaced along the perfusion line. Left ventricular pressure, coronaryflow and coronary perfusion pressure are recorded using a TEAC R-7 1recorder, digitized at 1000 Hz and analyzed off-line withDataQ-Instruments/CODAS software, which allow quantification of themaximum rate of increase of LVP during systole (dP/dt_(max)).

Hearts are perfused with Krebs-Henseleit solution gassed with 95% O₂ and5% CO₂ of the following composition: 17.7 mM sodium bicarbonate, 127 mMNaCl, 5.1 mM KCl, 1.5 mM CaCl2, 1.26 mM MgCl2, 11 mM D-glucose,supplemented with 5 μg/mL lidocaine.

The test compound or pharmaceutical compositions are diluted in bufferimmediately prior to use. Hearts are allowed to stabilize for 30 min,and baseline parameters are recorded. Typically, coronary flow isadjusted within the first 10 min and kept constant from thereon. After30 min stabilization, hearts are randomly assigned to one of thetreatment groups, and subjected to 30 min global, no-flow ischemia,followed by 30 min of reperfusion (I/R). Pacing of the hearts is stoppedat the beginning of the ischemic period and restarted after the thirdminute of reperfusion.

Hearts in a control group are perfused with a buffer for an additional29 min after stabilization. Treated hearts are exposed to a testcompound or pharmaceutical composition (e.g., 1 μM final concentrationfor about 20 min followed by a 10 min buffer wash-out period).

In all hearts, pacing is suspended at the onset of ischemia andrestarted 3 minutes following reperfusion. As isolated heartpreparations may deteriorate over time (typically after 2-2.5 hoursperfusion), the re-flow duration is limited to 30 minutes in order tominimize the effects produced by crystalloid perfusion on heartperformance, and consistently with other reports.

Assessment of ventricular function: To obtain the maximal developed LVP,the volume of the intra-ventricular balloon is adjusted to anend-diastolic LVP of 10 mmHg during the stabilization period, asreported in Paolocci, supra, and Hare et al., J. Clin. Invest. 1998,101, 1424-31. Changes in developed LVP, dP/dt_(max) and theend-diastolic value induced by the I/R protocol are continuouslymonitored. The difference between the end-diastolic LVP (EDLVP) beforethe end of the ischemic period and during pre-ischemic conditions isused as an index of the extent of contracture development. Maximalrecovery of developed LVP and dP/dt_(max) during reperfusion is comparedwith respective pre-ischemic values.

Assessment of myocardial injury: Enzyme release is a measure of severemyocardial injury that has yet to progress to irreversible cell injury.Samples of coronary effluent (2 mL) are withdrawn with a catheterinserted into the right ventricle via the pulmonary artery. Samples aretaken immediately before ischemia and at 3, 6, 10, 20 and 30 min ofreperfusion. LDH release is measured as previously described byBergmeyer et al., Verlag Chemie 1974. Data are expressed as cumulativevalues for the entire reflow period.

To corroborate the data relative to myocardial injury, determined by LDHrelease, infarct areas are also assessed in a blinded fashion. At theend of the course (30 min reperfusion), each heart is rapidly removedfrom the perfusion apparatus, and the LV dissected into 2-3 mmcircumferential slices. Following 15 min of incubation at 37° C. in 0.1%solution of nitro blue tetrazolium in phosphate buffer as described inMa et al., Proc. Natl. Acad. Sci. 1999, 96, 14617-14622, unstainednecrotic tissue is separated from the stained viable tissue. The areasof viable and necrotic tissue are carefully separated by an independentobserver who is not aware of the origin of the hearts. The weight of thenecrotic and non-necrotic tissues is then determined and the necroticmass expressed as a percentage of total left ventricular mass.

Data may be subjected to statistical methods such as ANOVA followed bythe Bonferroni correction for post hoc t tests.

Cancer

Anticancer activities of compounds described herein can be assessedusing in vivo mouse xenograft models using methods described in NorrisA. J. et al., Intl. J. Cancer 2008, 122, 1905-1910 and Stoyanovsky, D.A. et al., J. Med. Chem. 2004, 47, 210-217).

Mice are inoculated with appropriate tumor cells by subcutaneousinjection into the lower flank. Therapy can be started after 1-3 weekswhen the tumors have reached an average volume of ˜50-60 mm³. Tumordiameters are measured with digital calipers, and the tumor volume iscalculated. The anti-tumor efficacy of test compounds is assessed bycomparison of tumor size in test group to that in the control group.

Example 11 In Vivo Animal Studies (Acute Treatment, IntravenousInfusion)

This example demonstrates the efficacy of compounds and pharmaceuticalcompositions described herein to lower pulmonary artery pressure in ratswith monocrotaline-induced PH.

Rats (250-250 g) are anesthetized via an intra-muscular (i.m.) injectionof ketamine/xylazine (80/10 mg/kg). A half dose (40 mg/kg ketamine/5mg/kg xylazine) is given as supplemental anesthesia as needed. Animalsare placed on a heating pad set to maintain body temperature atapproximately 37° C. Body temperature is monitored throughout theexperiment. Once consciousness is lost, a pressure transducer isinserted into a femoral artery to measure arterial blood pressure. Afluid filled catheter is inserted through the right jugular vein intothe pulmonary artery to measure pulmonary artery pressure via a pressuretransducer. A cannula is placed into the left jugular vein for dosing.

Monocrotaline is administered via a single subcutaneous injection (60mg/kg) approximately 3 weeks prior to the terminal procedure. A baselinepulmonary artery pressure of >30 mmHg is required to initiate study ofthe compounds described herein. A nitroxy donor or a compound orpharmaceutical composition as described herein is administeredintravenously in a dose-escalation manner in 20 minute intervals fromdoses of 10 to 300 μg/kg/min. Hemodynamic indices, including MAP (meanarterial pressure), SAP (systolic arterial pressure), DAP (diastolicarterial pressure), HP (heart rate), MPAP (mean pulmonary arterialpressure), SPAP (systolic arterial pressure), DPAP (diastolic pulmonaryarterial pressure), are measured. The results of test compounds areillustrated in FIG. 1, FIG. 2 and FIG. 3.

For the terminal procedure, after surgical instrumentation and anapproximate 10 minute pre-dose equilibration period, test compound orpharmaceutical composition solutions are infused via jugular veincatheter. At the end of the experiment, rats are euthanized underanesthesia via pentobarbital overdose.

Example 12 In Vivo Animal Studies (Acute Treatment, Intravenous Infusionor Inhaled Administration)

This example demonstrates the efficacy of the compounds andpharmaceutical compositions described herein to lower pulmonary arterypressure in dogs with hypoxia-induced PH.

Healthy dogs (10-15 kg) are anesthetized with pentobarbital (20-40mg/kg. intravenously) and anesthesia is maintained by continuousinfusion of pentobarbital at rate of 5-10 mg/kg/h. Dogs are intubatedvia a tracheotomy, and artificially respired (while monitoring inspiredoxygen and expired CO₂). The left femoral vein and artery are cannulatedfor dose administration and arterial blood pressure recording. The rightjugular vein is cannulated with a pulmonary artery pressure catheter(Swan Ganz catheter), to measure both pulmonary arterial pressure (PAP)and pulmonary wedge pressure (PWP). This catheter is also used formeasurement of cardiac output via thermodilution techniques followingrapid injection of cold 5 mL saline. Electrocardiograms are monitoredthroughout the experiment.

During the baseline and control measurements inspired oxygen ismaintained at 40%. Hypoxia is induced by adding nitrogen to therespiratory gas at a rate sufficient to reduce respired oxygen to 10%(FiO2=10%). Each hypoxic condition is maintained for 15-30 minutes andthen normoxic (FiO2=40%) control condition is returned. Each dose oftest compound or pharmaceutical composition is intravenouslyadministered during the 30 minute hypoxic condition; no drug is infusedduring the subsequent normoxia until the next dose is given. Testcompounds or pharmaceutical compositions are given intravenously in therange of 1 to 100 μg/kg/min and various hemodynamic indices arerecorded. Alternatively, in this experiment test compounds orpharmaceutical compostions are administered using an inhalationnebulizer at dose levels of 0.1-1 g/kg in 5-10 time period during eachhypoxia period.

Example 13 In Vivo Animal Studies (Chronic Treatment, ContinuousIntravenous Infusion)

This example demonstrates the efficacy of the compounds andpharmaceutical compositions described herein to retard the progressionof disease in rats with monocrotaline-induced PH.

Rats (200-250 g) are surgically implanted with a pressure transducerequipped telemetry transmitter. The transmitter assembly is securedinternally; the fluid-filled catheter is placed into the jugular veinwith the tip of the pressure transducer positioned in the rightventricle for collection of right ventricular pressure (RVP) data.Additionally, all animals, with the exception of the sham group, areimplanted with femoral vein cannulas for the purposes of dosing.

Monocrotaline (MCT) is administered to vehicle-control animals bysubcutaneous injection. One week following the MCT injection, thevehicle-control animals are administered saline or a low or high dose ofa test compound or pharmaceutical composition by continuous intravenousinfusion for two weeks. The test and vehicle control article areadministered by external pump. Weekly clinical observations areperformed on animals.

For cardiovascular evaluations, RVP data is collected with animalsallowed free movement in the home cage. The animals are monitored for atleast 24 hours prior to MCT administration. RVP is also monitored at 24hours following the end of the two week infusion, and occurs for atleast 24 hours. All animals are necropsied at the end of the study.Weights of lungs and pulmonary artery, heart and each individual chamberare evaluated. The weights of the heart, LV, RV, and ratio to bodyweight are reported. The small pulmonary arteries from each animal areevaluated for medial thickness, neointima, and smooth musclehypertrophy.

Example 14 In Vivo Animal Studies (Chronic Treatment, OralAdministration)

This example demonstrates the efficacy of the compounds andpharmaceutical compositions described herein to retard the progressionof disease in rats with monocrotaline-induced PH.

The general methodology for this experiment is similar to that ofExample 12 above. One difference is that the route of administration isoral, with a dosing regimen of once to four times daily at dose levelsof 0.1-1 g/kg.

Example 15 In Vivo Animal Studies (Chronic Treatment, ContinuousIntravenous Infusion)

This example demonstrates the efficacy of the compounds andpharmaceutical compositions described herein to reverse the progressionof disease in rats with monocrotaline-induced PH.

In this study, rats (200-250 g) rats are surgically implanted with apressure transducer equipped telemetry transmitter. The transmitterassembly is secured internally; the fluid-filled catheter is placed intothe jugular vein with the tip of the pressure transducer positioned inthe right ventricle for collection of right ventricular pressure (RVP)data. Additionally, all animals, with exception of sham group, areimplanted with femoral vein cannulas for the purposes of dosing.

The vehicle and control article, monocrotaline (MCT), are administeredby subcutaneous injection. Three weeks following the MCT injection,animals are administered saline or a low or high dose of a test compoundor pharmaceutical composition by continuous intravenous infusion forthree weeks. The test compound or pharmaceutical composition and vehiclecontrol article are administered by external pump. Weekly clinicalobservations are performed on the animals.

For cardiovascular evaluations, RVP data is collected with animalsallowed free movement in the home cage. The animals are monitored for atleast 24 hours prior to MCT administration. RVP is also monitored for atleast 24 hours following the end of the two week infusion. All animalsare necropsied at the end of the study. Weights of lungs and pulmonaryartery, heart and each individual chamber are evaluated. The weights ofthe heart, LV, RV, and ratio to body weight are reported. The smallpulmonary arteries from each animal are evaluated for medial thickness,neointima, and smooth muscle hypertrophy.

Example 16 In Vivo Animal Studies (Chronic Treatment, OralAdministration)

This example demonstrates the efficacy of the compounds andpharmaceutical compositions described herein to reverse the progressionof disease in rats with monocrotaline-induced PH.

The general methodology is similar to that of Example 14, with theexception that the route of administration is oral, with a dosingregimen of one to four times daily at dose levels of 0.1-1 g/kg.

Example 17 In Vivo Animal Studies (Chronic Treatment, InhaledAdministration)

This example demonstrates the efficacy of the compounds andpharmaceutical compositions described herein to retard progression ofdisease in rats with monocrotaline-induced PH.

The general methodology is similar to that of Example 12 above, with theexception that the route of administration is via inhalation, with adosing regimen of one to four times daily at dose levels of 0.1-1 g/kg.

Example 18 In Vivo Animal Studies (Chronic Treatment, InhaledAdministration)

This example demonstrates the efficacy of the compounds andpharmaceutical compositions described herein to reverse the progressionof disease in rats with monocrotaline-induced PH.

The general methodology is similar to that of Example 12, with theexception that the route of administration is via inhalation, with adosing regimen of one to four times daily at dose levels of 0.1-1 g/kg.

Example 19 In Vivo Animal Studies (Acute Treatment, Intravenous Infusionand Inhaled Administration)

This example demonstrates the efficacy of the compounds andpharmaceutical compositions described herein to lower pulmonary arterypressure in dogs with thromboxane-induced PH.

Experimental PH is induced by continuous infusion of a thromboxane A2receptor agonist analog (for example U46619, Tocris Bioscience). Thethromboxane A2 receptor agonist analog infusion rate (0.1-1 mg/kg/min)is adjusted to maintain a systolic pulmonary artery pressure (PAP) at 40mmHg in anesthetized and mechanically ventilated dogs. The left femoralvein and artery are cannulated for dose administration and arterialblood pressure recording. The right jugular vein is cannulated with apulmonary artery pressure catheter (Swan Ganz catheter), to measure bothpulmonary arterial pressure (PAP) and pulmonary wedge pressure (PWP).This catheter is also used for measurement of cardiac output viathermodilution techniques following rapid injection of cold 5 mL saline.Electrocardiograms are monitored throughout the experiment.

Once a stable steady-state in hemodynamic is achieved, various doses ofthe test compounds or pharmaceutical compositions are givenintravenously at dose rates in the range of 1 to 100 μg/kg/min andvarious hemodynamic indices are recorded. Alternatively, in thisexperiment the test compounds or pharmaceutical compositions areadministered using an inhalation nebulizer at dose levels of 0.1-1 g/kgin 5-10 time period.

Example 20 In Vivo Human Studies (Acute Treatment, Intravenous Infusionand Inhaled Administration)

This example demonstrates the efficacy of HNO donors to lower pulmonaryartery pressure in human subjects with various causes of pulmonaryhypertension.

Patients (either gender) with various causes of pulmonary hypertensionare selected for this study. Baseline hemodynamic characteristics of thepatients are assessed by collected various hemodynamic indices utilizingright heart catheterization (e.g. right atrial pressure, mean pulmonaryartery pressure, cardiac index), and blood gas profiling. Cardiac rhythmis monitored using continuous electrocardiography, and arterial pressureis monitored using a pressure cuff. Patients are tested forreversibility of pulmonary hypertension using nitric oxide (NO) byinhalation. Hemodynamic indices are then reassessed. Once all indiceshave returned to baseline upon cessation of NO delivery, and a baselineis established, various doses of HNO donors are given intravenously atdose rates in the range of 1 to 100 μg/kg/min (either continuous dose orin a dose-escalation fashion) and various hemodynamic indices arerecorded. Alternatively, in this experiment HNO donors are administeredusing an inhalation nebulizer at dose levels of 0.1-1 g/kg in 5-10minute time period. Hemodynamic indices are assessed at various timepoints during the infusion period. A few patients receive placeboinstead of HNO donor in a double-blind randomized fashion. From the datacollected during various periods of the trial, the pulmonary andsystemic vascular resistances are calculated.

Example 21 Human Clinical Trials to Determine Ability of Compounds orPharmaceutical Compositions to Treat, Prevent and/or Delay Onset and/orDevelopment of a Disease or Condition

Any of the compounds and pharmaceutical compositions described hereincan also be tested in humans to determine the ability of the compoundsor pharmaceutical compositions to treat, prevent and/or delay the onsetand/or the development of a disease or condition. Standard methods canbe used for these clinical trials. In one exemplary method, individualswith a disease or condition described herein, such as congestive heartfailure, are enrolled in a tolerability, pharmacokinetics andpharmacodynamics phase I study of a therapy using the compoundsdescribed herein in standard protocols. Then a phase II, double-blindrandomized controlled trial is performed to determine the efficacy ofthe compounds using standard protocols.

It will be apparent to those skilled in the art that specificembodiments of the invention may be directed to one, some or all of theabove- and below-indicated embodiments in any combination.

While the invention has been described in some detail by way ofillustration and example for purposes of clarity of understanding, itshould be understood by those skilled in the art that various changesmay be made and equivalents may be substituted without departing fromthe true spirit and scope of the invention. Therefore, the descriptionand examples should not be construed as limiting the scope of theinvention.

All references, publications, patents, and patent applications disclosedherein are hereby incorporated by reference in their entirety.

1. A compound of formula (I)

or a pharmaceutically acceptable salt, hydrate, or solvate thereofwherein: L is a bond, —SO₂— or —O—; Y is alkyl, aryl, heteroaryl orbenzyl, wherein said alkyl, aryl, heteroaryl and benzyl are substitutedwith one or more substituents independently selected from W; W is halo,—CN, —NO₂, —COR^(S), —COOR^(S), —CONR³R⁴, —CH(C(O)R³)₂, —SO₂R³ or —COX,wherein X is halo, and R³ and R⁴ are independently alkyl or aryl, or R³and R⁴ are taken together to form a cycloalkyl or heterocycloalkyl,wherein said cycloalkyl and heterocycloalkyl are unsubstituted orsubstituted with one or more substituents; R¹ and R² are independentlyhydrogen, alkyl, heterocycloalkyl, aryl, benzyl, alkoxy, aryloxy,benzyloxy, —NR⁵R⁶, —N(OR⁵)R⁶, —NR⁵C(O)R⁶ or —O-heterocycloalkyl, whereinsaid alkyl, heterocycloalkyl, aryl, benzyl, alkoxy, aryloxy, benzyloxy,—N(OR⁵)R⁶, —NR⁵C(O)R⁶ and —O-heterocycloalkyl are unsubstituted orsubstituted with one or more substituents; and R⁵ and R⁶ areindependently alkyl or aryl, where said alkyl and aryl are unsubstitutedor substituted with one or more substituent;. provided that when L is—SO₂—, R² is phenyl or alkyl, and Y is phenyl substituted with onesubstituent selected from W, then W is not 4-chloro or 4-nitro; andprovided that when L is —SO₂—, R² is alkyl, and Y is phenyl substitutedwith two or three substituents independently selected from W, then twoof the substituents are not 3-nitro and 5-nitro.
 2. The compound ofclaim 1, wherein L is —SO₂—.
 3. The compound of claim 1, wherein Y isaryl substituted with one or more substituents independently selectedfrom W.
 4. The compound of claim 1, wherein Y is aryl substituted withone, two or three substituents independently selected from W.
 5. Thecompound of claim 1, wherein Y is phenyl substituted with one or moresubstituents independently selected from W.
 6. The compound of claim 1,wherein Y is heteroaryl and said heteroaryl is unsubstituted orsubstituted with one or more substituents independently selected from W.7. The compound of claim 1, wherein Y is benzyl and said benzyl issubstituted with one or more substituents independently selected from W.8. The compound of claim 1, wherein W is halo, —SO₂R³ or —NO₂.
 9. Thecompound of claim 1, wherein W is chloro, bromo, fluoro or —NO₂.
 10. Thecompound of claim 1, wherein R¹ and R² are independently alkyl,heterocycloalkyl, alkoxy, phenyl or benzyloxy, wherein said alkyl,heterocycloalkyl, alkoxy, phenyl and benzyoxy are unsubstituted orsubstituted with one or more substituents independently selected fromhalo, alkyl, nitro, alkylsulfonyl and trihalomethyl.
 11. The compound ofclaim 1, wherein: R¹ is alkyl, heterocycloalkyl, alkoxy, phenyl orbenzyloxy, wherein said alkyl is unsubstituted or substituted with oneor more halos, and said heterocycloalkyl is unsubstituted or substitutedwith alkyl; and R² is alkyl or aryl.
 12. The compound of claim 1,wherein R⁵ and R⁶ are independently C₁-C₆ alkyl and said alkyl isunsubstituted or substituted with one or more substituents.
 13. Thecompound of claim 1, wherein R⁵ and R⁶ are independently C₁-C₆ alkyl andsaid alkyl is unsubstituted or substituted with one or more substituentsindependently selected from alkoxy, heteroaryl and —C(O)OR¹¹.
 14. Thecompound of claim 2, wherein Y is alkyl, wherein said alkyl issubstituted with one or more substituents independently selected from W.15. The compound of claim 2, wherein Y is alkyl, wherein said alkyl issubstituted with one or more halos.
 16. The compound of claim 12,wherein R¹ and R² are independently alkyl, heterocycloalkyl, alkoxy,phenyl, benzyl or benzyloxy, wherein said alkyl, heterocycloalkyl,alkoxy, phenyl, benzyl and benzyloxy are unsubstituted or substitutedwith one or more substituents independently selected from halo, alkyl,nitro, alkylsulfonyl, trihalomethyl, phenyl, —C(O)OR¹¹, —C(O)R¹³,—OC(O)R¹³, —NR¹¹R¹², —NR¹¹C(O)OR¹³ and —OR¹¹.
 17. The compound of claim12, wherein: R¹ is alkyl or alkoxy; and R² is alkyl or phenyl, whereinsaid phenyl is unsubstituted or substituted with one or moresubstituents independently selected from halo, nitro, alkylsulfonyl andtrihalomethyl.
 18. The compound of claim 1, wherein the compound isselected from: N-(4-bromobenzenesulfonyl)-N-acetyloxy-acetamide,N-(2-bromobenzenesulfonyl)-N-acetyloxy-acetamide,N-(2-chlorobenzenesulfonyl)-N-acetyloxy-acetamide,N-(2-bromo-4,6-difluoro-benzenesulfonyl)-N-acetyloxy-acetamide,N-(2,6-dibromobenzenesulfonyl)-N-acetyloxy-acetamide,N-(2,6-dichlorobenzenesulfonyl)-N-acetyloxy-acetamide,N-(2,6-difluorobenzenesulfonyl)-N-acetyloxy-acetamide,N-(2-nitrobenzenesulfonyl)-N-acetyloxy-acetamide,N-(2,6-dichlorobenzenesulfonyl)-N-acetyloxy-benzamide,N-(2,6-dichlorobenzenesulfonyl)-N-acetyloxy-benzyl-carbamate,N-(2,6-dichlorobenzenesulfonyl)-N-acetyloxy-dichloroacetamide,N-(2,5-dichlorobenzenesulfonyl)-N-acetyloxy-trimethylacetamide,N-(2-nitrobenzenesulfonyl)-N-acetyloxy-trimethylacetamide,N-(2,6-dichlorobenzenesulfonyl)-N-acetyloxy-trimethylacetamide,N-(2-bromobenzenesulfonyl)-N-acetyloxy-tert-butyl-carbamate,N-(2,6-dichlorobenzenesulfonyl)-N-acetyloxy-tert-butyl-carbamate,N-(2,6-dibromobenzenesulfonyl)-N-acetyloxy-tert-butyl-carbamate,N-(2,6-dichlorobenzenesulfonyl)-N-4-nitrobenzoyloxy)-tert-butyl-carbamate,tert-butyl (acetyloxy)[(2-bromophenyl)sulfonyl]carbamate, tert-butyl(acetyloxy) {[2-(methylsulfonyl)phenyl]sulfonyl}carbamate, tert-butyl{[2-(methylsulfonyl)phenyl]sulfonyl}(propanoyloxy)carbamate, tert-butyl[(2-methylpropanoyl)oxy]{[2-(methylsulfonyl)phenyl]sulfonyl}carbamate,tert-butyl[(2,2-dimethylpropanoyl)oxy]{[2-(methylsulfonyl)phenyl]sulfonyl}-carbamate,tert-butyl{[2-(methylsulfonyl)phenyl]sulfonyl}[(phenylcarbonyl)oxy]carbamate,ethyl(acetyloxy) {[2-(methylsulfonyl)phenyl]sulfonyl}-carbamate,ethyl(acetyloxy)[(2-bromophenyl)sulfonyl]carbamate, benzyl(acetyloxy){[2-(methylsulfonyl)phenyl]sulfonyl}carbamate, benzyl{[2-(methylsulfonyl)phenyl]sulfonyl}(propanoyloxy)carbamate;N-[(2,2-dimethylpropanoyl)oxy]-4-methyl-N-{[2-(methylsulfonyl)phenyl]sulfonyl}-piperazine-1-carboxamide;N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido2-(acetyloxy)benzoate;N-[(tert-butoxy)carbonyl]1-benzofuran-2-sulfonamido2,2-dimethylpropanoate;N-[(tert-butoxy)carbonyl]1-benzofuran-2-sulfonamido acetate;N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamido benzoate;N-[(tert-butoxy)carbonyl]3-bromothiophene-2-sulfonamido2,2-dimethylpropanoate;N-[(tert-butoxy)carbonyl]3-chlorothiophene-2-sulfonamido2,2-dimethylpropanoate;N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamido 2-methylpropanoate;N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamido2,2-dimethylpropanoate;N-[(tert-butoxy)carbonyl](2-chlorobenzene)sulfonamido2,2-dimethylpropanoate;N-[(tert-butoxy)carbonyl][2-chloro-5-(dimethylcarbamoyl)benzene]sulfonamidoacetate;N-[(tert-butoxy)carbonyl](2-chlorobenzene)sulfonamido2-methylpropanoate; N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamido2-phenylacetate; N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamido2-methyl-2-phenylpropanoate;N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamido1-phenylcyclopentane-1-carboxylate;2-N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamido 1-tert-butylpyrrolidine-1,2-dicarboxylate;N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamido2-[4-(dimethylamino)phenyl]acetate;N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamido1-acetylpyrrolidine-2-carboxylate;N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamido(2S)-2-phenylpropanoate;N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamido(2R)-2-phenylpropanoate;N-[(tert-butoxy)carbonyl]-5-chlorothiophene-2-sulfonamido2-methylpropanoate;N-[(tert-butoxy)carbonyl]-5-chlorothiophene-2-sulfonamido2,2-dimethylpropanoate;N-[(tert-butoxy)carbonyl](3-methanesulfonylbenzene)sulfonamido2,2-dimethylpropanoate;N-[(tert-butoxy)carbonyl](3-methanesulfonylbenzene)sulfonamido2-methylpropanoate; N-[(tert-butoxy)carbonyl]pyridine-3-sulfonamido2,2-dimethylpropanoate; N-[(tert-butoxy)carbonyl]pyridine-3-sulfonamido2-methylpropanoate;N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido(2S)-2-{[(tert butoxy)carbonyl](methyl)amino}-4-methylpentanoate;N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido(2R)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanoate;N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanoate;N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene) sulfonamido2-{[(tert-butoxy)carbonyl](methyl)amino}acetate;N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}-3-methylbutanoate;N-[(tert-butoxy)carbonyl][(4-chlorophenyl)methane]sulfonamido2,2-dimethylpropanoate;N-[(benzyloxy)carbonyl](2-methanesulfonylbenzene)sulfonamido2,2-dimethylpropanoate;N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamidoN,N-dimethylcarbamate;N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamidoN,N-dimethylcarbamate;N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene) sulfonamidomorpholine-4-carboxylate;N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene) sulfonamido4-acetylpiperazine-1-carboxylate; tert-butyl N-{[cyclohexyl(methyl)carbamoyl]oxy}-N-[(2-methanesulfonylbenzene)sulfonyl]carbamate;1-N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido4-tert-butyl piperazine-1,4-dicarboxylate;N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene) sulfonamidoN-(2-methoxyethyl) carbamate;N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido N,Ndiethylcarbamate;N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamidoN-methoxy-N-methylcarbamate; tert-butylN-[(2-methanesulfonylbenzene)sulfonyl]-N-{[methyl(pyridin-3-ylmethyl)carbamoyl]oxy}carbamate;tert-butyl2-{[2-(tert-butoxy)-2-oxoethyl][({N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido}oxy)carbonyl]amino}acetate;4-{[({N-[(tert-butoxy)carbonyl](2-methanesulfonylbenzene)sulfonamido}oxy)-carbonyl]oxy}oxane;4-{[({N-[(tert-butoxy)carbonyl](2-bromobenzene)sulfonamido}oxy)carbonyl]oxy}oxane;1-({[(tert-butoxy)carbonyl][(methoxycarbonyl)oxy]amino}sulfonyl)-2-methanesulfonylbenzene;1-({[(tert-butoxy)carbonyl]({[(2-methoxyethoxy)carbonyl]oxy})amino}sulfonyl)-2-methanesulfonylbenzene;1-({[(tert-butoxy)carbonyl]({[2-(2-methoxyethoxy)ethoxy]carbonyl}oxy)amino}-sulfonyl)-2-methanesulfonylbenzene;1-({[(tert-butoxy)carbonyl]({[(1,3-diethoxypropan-2-yl)oxy]carbonyl}oxy)amino}-sulfonyl)-2-methanesulfonylbenzene;tert-butyl(acetyloxy)[(3-bromothiophen-2-yl)sulfolnyl]carbamate;N-[(tert-butoxy)carbonyl]1-benzofuran-2-sulfonamido2,2-dimethylpropanoate;N-[(tert-butoxy)carbonyl]1-benzofuran-2-sulfonamido acetate;N-[(tert-butoxy)carbonyl]3-bromothiophene-2-sulfonamido2,2-dimethylpropanoate;N-[(tert-butoxy)carbonyl]3-chlorothiophene-2-sulfonamido2,2-dimethylpropanoate;N-[(tert-butoxy)carbonyl]5-chlorothiophene-2-sulfonamido2-methylpropanoate;N-[(tert-butoxy)carbonyl]5-chlorothiophene-2-sulfonamido2,2-dimethylpropanoate; N-[(tert-butoxy)carbonyl]pyridine-3-sulfonamido2,2-dimethylpropanoate; N-[(tert-butoxy)carbonyl]pyridine-3-sulfonamido2-methylpropanoate; and pharmaceutically acceptable salts, hydrates andsolvates thereof.
 19. A compound of formula (II)

or a pharmaceutically acceptable salt, hydrate, or solvate thereofwherein: W is halo, —OH, —CN, —NO₂, —COR³, —COOR^(S), —CONR³R⁴,—CH(C(O)R³)₂, or —COX, wherein X is halo, and R³, R⁴ and R⁵ areindependently alkyl or aryl, or R³ and R⁴ are taken together to form acycloalkyl or heterocycloalkyl, wherein said cycloalkyl andheterocycloalkyl are unsubstituted or substituted with one or moresubstituents; R¹ and R² are independently hydrogen, alkyl,heterocycloalkyl, aryl, benzyl, alkoxy, aryloxy, benzyloxy or —NR⁶R⁷,wherein said alkyl, heterocycloalkyl, aryl, benzyl, alkoxy, aryloxy andbenzyloxy are unsubstituted or substituted with one or more substituentsindependently selected from halo, alkyl, nitro, alkylsulfonyl andtrihalomethyl; R⁶ and R⁷ are independently alkyl or aryl; provided thatwhen R¹ and R² are each phenyl, then W is not —CN; and provided thatwhen R¹ is phenylethyl and R² is methyl, then W is not chloro.
 20. Acompound of formula (Ia)

or a pharmaceutically acceptable salt, hydrate, or solvate thereofwherein: L is a bond, —SO₂— or —O—; Y is a heteroaryl, wherein saidheteroaryl is unsubstituted or substituted with one or more substituentsindependently selected from W; W is halo, —CN, —NO₂, —COR³, —COOR³,—CONR³R⁴, —CH(C(O)R³)₂, —SO₂R³ or —COX, wherein X is halo, and R³ and R⁴are independently alkyl or aryl, or R³ and R⁴ are taken together to forma cycloalkyl or heterocycloalkyl, wherein said cycloalkyl orheterocycloalkyl are unsubstituted or substituted with one or moresubstituents; R¹ and R² are independently hydrogen, alkyl,heterocycloalkyl, aryl, benzyl, alkoxy, aryloxy, benzyloxy or —NR⁵R⁶,wherein said alkyl, heterocycloalkyl, aryl, benzyl, alkoxy, aryloxy, andbenzyloxy are unsubstituted or substituted with one or more substituentsindependently selected from halo, alkyl, nitro, alkylsulfonyl andtrihalomethyl; and R⁵ and R⁶ are independently alkyl or aryl.
 21. Apharmaceutical composition comprising: a compound of claim 1; and apharmaceutically acceptable excipient.
 22. A method of treating adisease or condition selected from cardiovascular diseases, ischemia,reperfusion injury, cancerous disease, pulmonary hypertension andconditions responsive to nitroxyl therapy, comprising administering acompound of claim 1 to a subject in need thereof.
 23. The method ofclaim 22, wherein the disease or condition is a cardiovascular disease.24. The method of claim 23, wherein the cardiovascular disease is heartfailure.
 25. The method of claim 24, wherein the heart failure iscongestive heart failure.
 26. The method of claim 24, wherein the heartfailure is acute congestive heart failure.
 27. The method of claim 24,wherein the heart failure is acute decompensated heart failure.
 28. Themethod of claim 22, wherein the disease or condition is ischemia orreperfusion injury.
 29. The method of claim 22, wherein the disease orcondition is a cancerous disease.
 30. The method of claim 22, whereinthe disease or condition is breast cancer, pancreatic cancer, prostatecancer or colorectal cancer.
 31. A method of modulating in vivo nitroxyllevels, comprising administering a compound of claim 1 to a subject inneed thereof.
 32. A kit comprising: a compound of claim 1; andinstructions for treating a condition that is responsive to nitroxyltherapy.